JP6710754B2 - Novel ferroportin inhibitor - Google Patents

Description

The present invention relates to novel compounds of the general formula (AI), pharmaceutical compositions containing them, and in particular for use as ferroportin inhibitors, more particularly diseases caused by hepcidin deficiency or impaired iron metabolism, such as especially iron overload. It relates to its use as a medicament for use in the prophylaxis and/or treatment of conditions such as thalassemia and hemochromatosis in particular.

Iron is an essential trace element for almost all organisms and is particularly associated with growth and blood formation. In this case, the balance of iron metabolism is mainly regulated by the iron recovery level from hemoglobin of senescent red blood cells and the duodenal absorption level of dietary iron. The released iron is taken up in particular via the intestine via a specific transport system (DMT-1, ferroportin) and transferred to the blood circulation, whereby it is transferred to the appropriate tissues and organs (transferrin, transferrin receptor). Carried.

In the human body, elemental iron is, among other things, very important for oxygen transport, oxygen uptake, cellular function (eg, mitochondrial electron transfer, cognitive function, etc.), and ultimately for overall energy metabolism.

On average, the human body contains 4-5 g of iron, which is present in the stored or reserve iron in the form of the enzymes, hemoglobin and myoglobin, and ferritin and hemosiderin. About half (about 2 g) of this iron is present as heme iron bound to the hemoglobin of red blood cells. Due to the limited life span of these red blood cells (75-150 days), new ones are constantly being formed and old ones have to be degraded (more than 2 million red blood cells are formed per second). This high regenerative capacity is achieved by macrophages that phagocytose senescent red blood cells, lyse them and recycle the iron thus obtained for iron metabolism. Most of the iron needed for erythropoiesis (about 25 mg/day) is thus provided.

The daily iron requirement of human adults is 0.5-1.5 mg per day, and infants and pregnant women require 2-5 mg of iron per day. For example, daily iron loss due to desquamation of skin and epithelial cells is low. For example, increased iron loss occurs during menstrual bleeding in women. In general, about 1 mg of iron is lost per 2 ml of blood, so blood loss can significantly reduce iron levels. In healthy human adults, about 1 mg of normal daily iron loss is usually replaced via daily food intake that re-adjusts daily iron requirements to adequate levels.

Iron levels are regulated by absorption, the absorption rate of iron present in food is 6-12%, up to 25% in the case of iron deficiency. The absorption rate is regulated by the organism depending on the iron requirement and the size of the iron store. In this process, human organisms utilize both divalent and trivalent iron ions. Normally, iron(III) compounds are dissolved in the stomach at sufficiently acidic pH values and made available for absorption. Iron absorption is carried out by the mucosal cells in the upper small intestine. In this process, trivalent non-heme iron is first reduced to Fe(II) in the intestinal cell membrane for absorption, for example by ferric iron reductase (membrane bound duodenal cytochrome b), resulting in subsequent transport. It can be transported to enterocytes by the protein DMT1 (divalent metal transporter 1). In contrast, heme iron enters enterocytes through the cell membrane without any change. In enterocytes, iron is stored in ferritin as iron store or released into the blood by the transport protein ferroportin. Since hepcidin is an essential regulator of iron absorption, it plays a central role in this process. The ferrous iron transported into the blood by ferroportin is converted to ferric iron by oxidases (ceruloplasmin, hefaestin), which is then transported by transferrin to relevant places in the organism (eg, "Balancing"). acts: molecular control of mammalian iron metabolism". See MW Hentze, Cell 117, 2004, 285-297.).

Mammalian organisms cannot actively excrete iron. Iron metabolism is substantially regulated by hepcidin through cellular release of iron from macrophages, hepatocytes and enterocytes.

Hepcidin is a peptide hormone produced in the liver. The predominant active form has 25 amino acids (see, for example, “Hepcidin, a key regulator of iron metabolism and mediator of anaemia of inflammation”. T. Ganz, Blood 3-, 102, 78, 103). Two truncated forms have been found, hepcidin-22 and hepcidin-20. Hepcidin acts on the absorption of iron through the intestine and placenta and the release of iron from the reticuloendothelial system. In the body, hepcidin is synthesized in the liver from what is known as prohepcidin, which is encoded by a gene known as the HAMP gene. The formation of hepcidin is regulated in direct correlation with the iron levels of the organism, i.e. when the organism is supplied with sufficient iron and oxygen, more hepcidin is formed, at lower iron and oxygen levels or in red blood cells. When production is increased, less hepcidin is formed. In small intestinal mucosal cells and macrophages, hepcidin binds with the transport protein ferroportin, which conventionally transports iron recycled by phagocytosis from inside the cell into the blood.

The transport protein ferroportin is a 571 amino acid transmembrane protein formed in the liver, spleen, kidney, heart, intestine and placenta. In particular, ferroportin is localized in the basolateral membrane of intestinal epithelial cells. The ferroportin thus bound acts to deliver iron into the blood. In this case, ferroportin most likely transports iron as Fe ²⁺ . When hepcidin binds to ferroportin, ferroportin is transported to the interior of the cell, where its destruction occurs so that the release of iron reutilized by phagocytosis from the cell is almost completely blocked. If ferroportin is inactivated, for example by hepcidin, so that it is unable to deliver the iron stored in the mucosal cells, the stored iron is lost by the natural excretion of the cells via the stool. Therefore, when ferroportin is inactivated or inhibited by, for example, hepcidin, iron absorption in the intestine is reduced. Furthermore, ferroportin is significantly localized in the reticuloendothelial system (RES), to which macrophages also belong. Hepcidin plays an important role here when iron metabolism is impaired by chronic inflammation. In the case of inflammation, interleukin-6 is especially increased, triggering elevated hepcidin levels. As a result, more hepcidin binds to macrophage ferroportin, blocking the release of iron stores and ultimately leading to anemia of inflammation (ACD or AI).

On the other hand, lowering serum iron levels reduces hepcidin production in liver hepatocytes, resulting in less hepcidin released and thus less ferroportin that is inactivated and transports large amounts of accumulated iron into the serum. It becomes possible to do.

From it, it becomes clear that the hepcidin-ferroportin system directly regulates iron metabolism, so that impairment of the hepcidin regulatory mechanism has a direct effect on iron metabolism in the organism. In principle, the hepcidin-ferroportin regulatory mechanism works via two opposite principles:
On the one hand, an increase in hepcidin results in the inactivation of ferroportin, thus blocking the release of stored iron from the cells into the serum and thus lowering the serum iron level. In pathological cases, reduced serum iron levels lead to reduced hemoglobin levels, reduced erythropoiesis and thus iron deficiency anemia.

On the other hand, a decrease in hepcidin results in an increase in active ferroportin, which enhances the release of stored iron, for example enhanced iron uptake from food, thus increasing serum iron levels. In pathological cases, elevated iron levels lead to iron overload.

Iron overload conditions and diseases are characterized by excess iron levels. There, problems arise from excess serum iron levels resulting in unbound iron (NTBI) with transferrin. NTBI is rapidly and nonspecifically taken up by organs, leading to the accumulation of iron in tissues and organs. Iron overload causes many diseases and unwanted medical conditions, including heart, liver and endocrine damage. Furthermore, iron accumulation in the brain has been observed in patients suffering from neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. As a particularly detrimental aspect of excess free iron, the formation of unwanted radicals must be mentioned. In particular, iron(II) ions catalyze the formation of reactive oxygen species (ROS), especially by the Fenton reaction. These ROS cause DNA, lipid, protein and carbohydrate damage, which has a wide range of effects on cells, tissues and organs. The formation of ROS is well known and has been described in the literature to cause so-called oxidative stress.

Previously established existing methods for treating iron overload are based on the concept of reducing the amount of iron in the serum by increasing the removal of iron from the body. Others The most long-known and still routine treatment in healthy people consists of regularly scheduled phlebotomy (bleeding). When initially diagnosed, phlebotomy is usually planned fairly often, eg, once a week, until iron levels are within normal limits, followed by phlebotomy depending on the patient's iron overload rate. It is planned once a month or every 3 months.

Chelating agents can be used for patients who cannot tolerate routine blood sampling. For example, deferoxamine (desferrioxamine B, N′-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4- (Oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide or Desferal®) is a bacterial siderophore and is an established drug used in chelation therapy. Deferoxamine binds to iron in the bloodstream as a chelating agent and promotes its excretion via urine and feces. A typical treatment for chronic iron overload requires subcutaneous injections for more than 8-12 hours per day. Parenteral injectable compositions of desferrioxamine B salt are described, for example, in WO 1998/25887.

Two new drugs approved for use in patients undergoing regular blood transfusions to treat thalassemia that result in the development of iron overload are deferasirox and deferiprone.

For example, deferasirox (Exjade (registered trademark), 4-(3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazole-1) described in WO 1997/49395 is used. -Yl) benzoic acid) and deferiprone (Feriprox (registered trademark), 3-hydroxy-1,2-dimethylpyridin-4(1H)-one) also act as iron chelating agents. It is suitable.

Additional compounds have been described that act as iron chelators for use in the treatment of iron overload. For example, WO 2013/142258 relates to encapsulated particles of diethylenetriaminepentaacetic acid (DTPA) and zinc salts. WO 2003/041709 relates to 4-hydroxy-2-alkylquinolines such as 4-hydroxy-2-nonylquinoline as iron chelating agents. WO 1998/09626 relates to chelating agents for treating iron overload conditions based on dithiocarbamate-containing compositions.

WO 2015/077655 Desferithiocin derivatives of formula (A) or (J) for use in the treatment of iron overload diseases

Regarding According to WO 2015/077655, the desferrithiocin derivative is found to act as an iron chelating agent.

WO 2005/051411 is described as acting as an iron chelating agent and used for the treatment of iron overload diseases

, A novel antibiotic or antifungal agent based on oxachelin and its derivatives.

A drawback in the treatment of iron overload with chelation therapy is the removal of chelated iron from the body if iron overload has already occurred instead of preventing the development of disorders. Furthermore, established drugs for iron chelation therapy are known to exhibit toxic potential.

In particular, it can be expected that modern approaches will increasingly replace this method, with increasing knowledge of the underlying mechanisms and the development of appropriate therapeutic methods based on such knowledge. Compounds having an inhibitory or supporting effect on hepcidin agonists or biochemical regulatory pathways in iron metabolism are basically known from the prior art.

For example, in known iron overload diseases such as hemochromatosis, iron deficiency can occur when hepcidin expression is inhibited by a genetic defect. Hemochromatosis is an iron overload disease caused by mutations in the genes that control hepcidin synthesis or the hepcidin gene itself. When hepcidin levels are low or absent in these patients, the amount of active ferroportin is increased, dietary iron absorption is increased, resulting in severe iron overload that causes heart, liver and endocrine damage. A hepcidin mimetic peptide, a peptide that also binds and inactivates ferroportin, has been shown to effectively reverse tissue iron accumulation in a model of hepcidin knockout mouse type 2 (juvenile) hemochromatosis (Ramos et al., Blood 2012).

In the known iron overload disease β-thalassemia, mutations in the β-globin gene produce sufficient numbers of red blood cells for reduced hemoglobin production and ineffective erythropoiesis, i.e., damage and death of developing red blood cells in the bone marrow. Cause that you cannot. This causes an upregulation of the rate of erythropoiesis and a decrease in hepcidin levels, making more iron available for increased erythropoietic activity. This maladaptive response results in iron overload due to reduced hepcidin levels and, as noted above, results in an increased amount of active ferroportin that increases absorption of dietary iron. Thalassemia red blood cells have a shortened half-life due to an unbalanced ratio of toxicity of α- and β-hemoglobin-subunits. The use of hepcidin mimetic peptides has also been described in the treatment of β-thalassemia, the basis for treatment being based on increased hepcidin activity leading to iron restriction and reduced iron-mediated damage in erythrocytes. Administration of the hepcidin mimetic peptide to th3/+ mice, a model of non-transfusion-dependent β-thalassemia, resulted in reduced ineffective erythropoiesis, increased red blood cell survival and improved anemia. In this model, prevention of iron overload by reducing dietary iron absorption was found to be an added benefit of hepcidin mimetic therapy (Gardenghi et al, 2010; Casu et al 2013).

The therapeutic approaches described are hampered by acting directly via the primary modulator hepcidin by providing a hepcidin mimetic or hepcidin agonist, i.e. by acting in the sense of a hepcidin surrogate or feed. It is based on its direct involvement in iron metabolism pathways. This approach is based on the therapies to treat iron overload, or excess serum iron levels, by inhibiting ferroportin through the hepcidin inactivation mechanism and thus blocking excess iron absorption.

Further known iron overload related diseases are diseases with ineffective erythropoiesis such as myelodysplastic syndrome (also known as MDS or myelodysplasia), polycythemia vera.

In addition, mutations in genes involved in the perception of systemic iron stores, such as hepcidin (Hamp1), hemochromatosis protein (HFE), hemojuvelin (HJV) and transferrin receptor 2 (TFR2), were detected in mice and humans. cause. Therefore, HFE and gene mutations, chronic hemolysis-related diseases, sickle cell diseases, erythrocyte membrane disorders and glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency), erythropoietic porphyria and Friedreich's ataxia. Diseases associated with. In addition, subgroups of iron overload include transfusional iron overload, iron poisoning, pulmonary hemophilia, osteopenia, insulin resistance, African iron overload, Hallerholden-Spatz syndrome, hyperferritinemia, ceruloplasmin deficiency, neonatal hemorrhage. Chromatosis and erythrocyte disorders, including thalassemia, alpha thalassemia, intermediate thalassemia, sickle cell disease and myelodysplastic syndrome.

Additional diseases and/or disorders and/or disease states associated with elevated iron levels include, but are not limited to, ataxia, Friedreich's ataxia, age-related macular degeneration, age-related cataract, age-related retinal disease and nerves. Included are diseases with elevated iron levels, including degenerative diseases, such neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, pantothenate kinase-related neurodegeneration, restless leg syndrome and Huntington's disease.

Hepcidin is a host defense peptide and represents a component of the innate immune system that responds to invading organisms.

Many bacteria are highly dependent on the iron supply from the host (the so-called siderophilic organism) and have been described as evolving the mechanism of capturing iron from local tissues. The ability of ferroportin inhibitors to limit the amount of iron available to such organisms can be an effective adjunct therapy. One such siderophyll organism is Vibrio vulnificus, which often causes rare but extremely severe infections in coastal areas in subjects with undiagnosed iron overload. Studies in animals inoculated with a lethal dose of Vibrio vulnificus showed that treatment with a hepcidin mimetic peptide that inactivates ferroportin, whether treatment was initiated before or after the onset of infection. Demonstrating nearly 100% viability in response to (Arezes et al 2015).

Known hepcidin mimetics include so-called minihepcidin, which is described, for example, in WO 2013/086143. Minihepcidin is a small synthetic peptide analog of the hepcidin N-terminus that is important for hepcidin to interact with ferroportin. Minihepcidin was developed based on the finding that the first 9 amino acids of hepcidin (DTHFPICIF) were found to be sufficient for in vitro activity (measured as ferroportin-GFP degradation). Minihepcidin has a modified hepcidin-9 amino acid sequence that exhibits improved resistance to proteolysis and enhanced biophysical interaction with ferroportin. Minihepcidin is described as being useful in the treatment of human iron overload conditions caused by hepcidin deficiency.

WO 2015/069660 describes a method of increasing hepcidin expression for treating iron overload by reducing non-transferrin bound iron (NTBI) by administering modified iron bound/releasing transferrin. There is.

All of the compounds described which act as hepcidin agonists, hepcidin mimetics or ferroportin inhibitors etc. are relatively high molecular weight compounds, especially those obtained primarily by genetic engineering. Biomolecular interactions and various additional approaches based on biomolecules have been described. The drawback is the complex preparation and high sensitivity of such biomolecular compounds. In particular, ferroportin antibody-based methods are not sufficiently efficient because the ferroportin, which is inhibited by the antibody, is permanently replicated by the organism and thus the inhibition does not last long enough to achieve the desired therapeutic effect.

Also known are low molecular weight compounds that can play a role in iron metabolism and have an inhibitory or promoting effect.

For example, WO 2008/151288, WO 2008/118790, WO 2008/115999 and WO 2008/109840 are compounds that act as divalent metal transporter-1 (DMT1) inhibitors. , And their use for treating iron disorders such as thalassemia or hemochromatosis.

WO 2008/123093 relates to agents for preventing or treating iron overload disorders, including 22β-methoxyolean-12-ene-3β,24(4β)-diol.

EP1074254 and EP1072265 relate to the use of catechins and flavonoid structured plant polyphenols for treating iron overload.

WO 2011/029832 relates to thiazole and oxazole compounds which have been described as acting as hepcidin antagonists and thus suitable for use for treating iron deficiency diseases. There, it is described that hepcidin antagonistic activity inhibits the inhibition of ferroportin by hepcidin, which is the opposite effect that the present inventors have found for the novel thiazole and oxazole compounds described herein. is there.

The compounds based on the structure of the general formula of the invention have not been previously disclosed for their activity as ferroportin inhibitors or for use in the prevention and treatment of iron metabolism disorders associated with elevated iron levels such as iron overload.

U.S. Patent Application Publication No. 2004/0138268, U.S. Patent Application Publication No. 2011/0224136, Chinese Patent No. 10350857, International Publication No. 2006/062224, International Publication No. 2015/051362, European Patent No. 1953145, International Publication No. 2009/154739, British Patent No. 937878, International Publication No. 2011/023722, International Publication No. 2010/020556, International Publication No. 2005/011685, International Publication No. 00. /56724, International Publication No. 2010/036632, International Publication No. 2005/014576, International Publication No. 2013/067578, International Publication No. 2005/116355 or Zou Yiquan et al. "Discovery of pyriazole as C-terminus of selective BACE1 inhibitors"; Eur. J. of Medicinal Chemistry 68 (2013) 270-283, Tussing-Humphreys et al. "Rethinking Iron Regulation and Assessment in Iron Definition, Anemia of Chronic Disease, and Obesity: Introducing Hepcidin". Academia of Nutrition and Dietetics (2012), Vol. 122, No. 3,391-400, Riordan et al. "Bleomycin analogs. Synthesis and proton NMR spectral assignments of thiazole amides related to bleomycin A2(1)"; Heterocyclic Chem. 18, 1213 (1981), Hideaki Sasaki "Synthesis of a novel bis(2,4'-bithiazole) derivative as a Co(II)-activated DNA clearing agent." Pharm. Bull. 42(8) 1685-1687 (1994), and Ballell et al. "Fueling open-source drug discovery. 177 small-molecule leads against tuberculosis"; Chemmed Chem 2013, 8, 313-321 describe compounds of different medical uses and mechanisms of action.

International Publication No. 1998/25887 International Publication No. 1997/49395 International Publication No. 2013/142258 International Publication No. 2003/041709 International Publication No. 1998/09626 International Publication No. 2015/077655 International Publication No. 2005/051411 International publication 2013/0886143 International Publication No. 2015/069660 International Publication No. 2008/151288 International Publication No. 2008/118790 International Publication No. 2008/115999 International Publication No. 2008/109840 International Publication No. 2008/123093 European Patent No. 1074254 European Patent No. 1072265 International Publication No. 2011/029832 U.S. Patent Application Publication No. 2004/0138268 U.S. Patent Application Publication No. 2011/0224136 Chinese Patent No. 10350857 International Publication No. 2006/062224 International Publication No. 2015/051362 European Patent No. 1953145 International Publication No. 2009/154739 British Patent No. 937878 International Publication No. 2011/023722 International Publication No. 2010/020556 International Publication No. 2005/011685 International Publication No. 00/56724 International Publication No. 2010/036632 International Publication No. 2005/014576 International Publication No. 2013/067578 International Publication No. 2005/116355

"Balanced acts: molecular control of mammalian iron metabolism". M. W. Hentze, Cell 117, 2004, 285-297. "Hepcidin, a key regulator of iron metabolism and mediator of anaemia of inflammation". T. Ganz, Blood, 102, 2003, 783-8. Ramos et al. , Blood 2012 Zou Yiquan et al. "Discovery of pyriazole as C-terminus of selective BACE1 inhibitors"; Eur. J. of Medicinal Chemistry 68 (2013) 270-283 Tussing-Humphreys et al. "Rethinking Iron Regulation and Assessment in Iron Definition, Anemia of Chronic Disease, and Obesity: Introducing Hepcidin". Academia of Nutrition and Dietetics (2012), Vol. 122, No. 3,391-400 Riordan et al. "Bleomycin analogs. Synthesis and proton NMR spectral assignments of thiazol amides related to bleomycin A2(1)"; Heterocyclic Chem. 18, 1213 (1981) Hideaki Sasaki "Synthesis of a novel bis(2,4'-bitiazole) derivative as a Co(II)-activated DNA cleaving agent"; Chem. Pharm. Bull. 42(8)1685-187 (1994) Ballell et al. "Fueling open-source drug discovery.177 small-molecule leads against tuberculosis"; ChemmedChem 2013, 8, 313-321.

OBJECTIVES The object of the present invention is in particular to provide novel therapeutically effective compounds which can be used in effective therapies, in particular for the prevention and treatment of iron metabolism disorders associated with elevated iron levels such as iron overload. Was to do. For further purposes, the new compounds should exhibit few side effects, have very low toxicity, be well bioavailable and compatible. In addition, these novel compounds, in contrast to known iron chelating compounds, prevent elevated iron levels, instead of removing excess iron from the body when iron overload has already occurred, and thus associated disorders. Should be suitable to prevent. For further purposes, the novel compound should have a well-defined structure (stoichiometry), be prepared by a simple synthetic process, with low sensitivity and long-term efficiency compared to known biomolecular compounds such as antibodies. It should show improvement.

This purpose has been found to act as a ferroportin inhibitor, and thus is suitable for use in inhibiting iron transport and thus is suitable for use in inhibiting iron transport and thus impaired iron metabolism with elevated iron levels. , Especially effective in the prevention and treatment of iron overload and diseases caused by deficiency of hepcidin, diseases associated with or caused by elevated iron levels or iron overload and diseases associated with ineffective erythropoiesis, This has been achieved by the development of new compounds according to the formulas defined herein, for example formula (AI) in particular.

FIG. 6 shows that an Fpn inhibitor induces ubiquitination and degradation of Fpn expressed in a mouse macrophage cell line. It is a figure which shows the typical iron efflux inhibition of hepcidin (IC50:0.086 micromol) and Example compound #127 (IC50:0.080 micromol). FIG. 6 shows serum iron kinetics in naive C57BL/6 mice injected intraperitoneally (ip) with synthetic hepcidin (5 mg/kg) for the times indicated. FIG. 6 shows serum iron levels in naive C57BL/6 mice treated with either the indicated amount of hepcidin (ip) or Example Compound 94 (Example Compound 94) (po) for 3 hours. is there. FIG. 6 shows dose-dependent blockade of iron absorption in anemia rats by Fpn inhibitor Example Compound #55. Complete enhancement of serum iron levels in b2m−/− mice by treatment with ferroportin inhibitor Example Compound #40/methylcellulose (A.) and Example Compound #94/cremophor EL® (B.) for 3 hours. It is a figure which shows various corrections.

The inventors have surprisingly found that certain compounds having the general structural formula (AI) as defined herein act as ferroportin inhibitors, thus effectively inhibiting iron transport, and thus especially For use in the treatment and/or prophylaxis of diseases caused by lack of hepcidin, diseases associated with ineffective erythropoiesis or disorders of iron metabolism leading to elevated iron levels, such as especially iron overload conditions (especially thalassemia and hemochromatosis) It has been found that it is particularly suitable for use as a pharmaceutical product. In particular, the new compounds have been found to be suitable for the treatment of thalassemia and hemochromatosis. The novel compounds are also suitable for use in treating diseases caused by pathologically low hepcidin levels and inhibiting iron transport.

Therefore, the present invention provides a novel compound of the general formula (AI),

(In the formula,
Het-2 is the formula

An optionally substituted bicyclic heteroaryl of
* Indicates a binding site with A ² ,
R ⁴ is 1, 2 or 3 -halogen,
-Cyano,
-Optionally substituted alkyl,
-Optionally substituted alkoxy, and -represents an optional substituent which can be independently selected from the group consisting of a carboxyl group;
X ¹ is C, N, S or O;
X ² is C or N;
X ³ is C, N, S or O;
X ⁴ is C, N or S,
However, there are 1 to 3 heteroatoms X,
X ¹ , X ³ and X ⁴ having the meaning of C or N can carry further substituents, eg preferably hydrogen or substituents as defined above for a substituted heteroaryl;
R ¹ is selected from the group consisting of —hydrogen and —optionally substituted alkyl;
Cycl is selected from the group consisting of -substituted aryl and -substituted or unsubstituted heteroaryl;
Q is C ₁ -C ₄ -alkyl which is capable of forming a condensed 5 or 6 membered ring with -hydrogen or -Cyl;
n is 0 or an integer of 1 to 8, preferably n is 0 or 1 to 4, preferably n is 0, 1, 2 or 3;
A ¹ is -optionally substituted alkanediyl;
A ² is -an optionally substituted alkanediyl or-a direct bond;
R ³ is - hydrogen, or - substituted is also alkyl; or A ¹ and R ^3, together with the nitrogen atom to which they are attached, 4-6 membered optionally substituted Or R ³ and A ² together with the nitrogen atom to which they are attached form an optionally substituted 4 to 7 membered ring;
Y ² is C or N,
-Both Y ² may be C, or-one Y ² may be N and one Y ² may be C)
Or, it relates to a pharmaceutically acceptable salt thereof.

In and throughout the present invention, the above substituents are defined as follows:
The optionally substituted alkyl preferably comprises:
A straight-chain or branched alkyl containing preferably 1 to 8, more preferably 1 to 6, particularly preferably 1 to 4, even more preferably 1, 2 or 3 carbon atoms.

The optionally substituted alkyl further comprises cycloalkyl, preferably containing from 3 to 8, more preferably 5 or 6 carbon atoms.

Examples of the alkyl residue containing 1 to 8 carbon atoms include methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, t- Butyl group, n-pentyl group, i-pentyl group, sec-pentyl group, t-pentyl group, 2-methylbutyl group, n-hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group , 4-methylpentyl group, 1-ethylbutyl group, 2-ethylbutyl group, 3-ethylbutyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethyl- 1-methylpropyl group, n-heptyl group, 1-methylhexyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl group, 1-ethylpentyl group, 2-ethyl Pentyl group, 3-ethylpentyl group, 4-ethylpentyl group, 1,1-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 4,4-dimethylpentyl group, 1-propyl Butyl group, n-octyl group, 1-methylheptyl group, 2-methylheptyl group, 3-methylheptyl group, 4-methylheptyl group, 5-methylheptyl group, 6-methylheptyl group, 1-ethylhexyl group, 2 -Ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 5-ethylhexyl group, 1,1-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group 5,5-dimethylhexyl group, 1-propylpentyl group, 2-propylpentyl group and the like. Those containing 1 to 6, preferably 1 to 4 carbon atoms are preferred, especially methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. More preferred is C ₁ -C ₃ alkyl, especially methyl, ethyl and i-propyl. Most preferred are C ₁ and C ₂ alkyls such as methyl and ethyl.

Cycloalkyl residues containing 3 to 8 carbon atoms preferably include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups. Cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group are preferred. Cyclopentyl and cyclohexyl groups are particularly preferred.

The optionally substituted alkyl substituents defined above are preferably, for example, optionally substituted cycloalkyl as defined above, hydroxy, an oxo group (=O), carboxy, Halogen as defined, cyano, alkoxy as defined below, optionally substituted acyl as defined below, optionally substituted acyloxy as defined below, optionally substituted as defined below Good aryl, optionally substituted heteroaryl as defined below, optionally substituted heterocyclyl as defined below, optionally substituted amino as defined below, substituted as defined below Optionally alkyl, aryl or heterocyclylsulfonyl (R—SO ₂ —) as well as alkylene groups such as especially methylene substituted ethyl groups (CH ₃ —(C═CH ₂ )— or

(In the formula, * represents a binding site), 1 to 3 of the same or different substituents selected from the group consisting of methylene groups, more preferably 1 or 2 of the same or different substituents. included. Preferably, the 1 to 3 substituents of alkyl are optionally substituted cycloalkyl, hydroxy, oxo (=O), carboxy, optionally substituted acyloxy, halogen, optionally substituted aryl. Optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino, optionally substituted alkyl, aryl or heterocyclylsulfonyl (R—SO ₂ —) and alkylene groups such as Particularly selected from methylene groups. Most preferred are 1 to 3 substituents of optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclyl and alkylene groups, for example alkyl, especially selected from methylene groups. Most preferred is one substituent of alkyl. Most preferred is one substituent of the alkyl substituents which is optionally substituted aryl or optionally substituted heteroaryl as defined below.

Halogen within the meaning of the invention comprises fluorine, chlorine, bromine and iodine, preferably fluorine or chlorine, with fluorine being most preferred.

Examples of linear or branched alkyl residues containing 1 to 8 carbon atoms substituted by halogen include:
Fluoromethyl group, difluoromethyl group, trifluoromethyl group, chloromethyl group, dichloromethyl group, trichloromethyl group, bromomethyl group, dibromomethyl group, tribromomethyl group, 1-fluoroethyl group, 1-chloroethyl group, 1- Bromoethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, difluoroethyl group (1,2-difluoroethyl group etc.), 1,2-dichloroethyl group, 1,2-dibromoethyl group, 2 , 2-difluoroethyl group, 2,2-dichloroethyl group, 2,2-dibromoethyl group, 2,2,2-trifluoroethyl group, heptafluoroethyl group, 1-fluoropropyl group, 1-chloropropyl group , 1-bromopropyl group, 2-fluoropropyl group, 2-chloropropyl group, 2-bromopropyl group, 3-fluoropropyl group, 3-chloropropyl group, 3-bromopropyl group, 1,2-difluoropropyl group 1,2-dichloropropyl group, 1,2-dibromopropyl group, 2,3-difluoropropyl group, 2,3-dichloropropyl group, 2,3-dibromopropyl group, 3,3,3-trifluoropropyl group Group, 2,2,3,3,3-pentafluoropropyl group, 2-fluorobutyl group, 2-chlorobutyl group, 2-bromobutyl group, 4-fluorobutyl group, 4-chlorobutyl group, 4-bromobutyl group, 4 ,4,4-trifluorobutyl group, 2,2,3,3,4,4,4-heptafluorobutyl group, perfluorobutyl group, 2-fluoropentyl group, 2-chloropentyl group, 2-bromopentyl group Group, 5-fluoropentyl group, 5-chloropentyl group, 5-bromopentyl group, perfluoropentyl group, 2-fluorohexyl group, 2-chlorohexyl group, 2-bromohexyl group, 6-fluorohexyl group, 6 -Chlorohexyl group, 6-bromohexyl group, perfluorohexyl group, 2-fluoroheptyl group, 2-chloroheptyl group, 2-bromoheptoyl group, 7-fluoroheptyl group, 7-chloroheptyl group, 7-bromoheptyl group , Perfluoroheptyl group and the like. Particular mention is made of fluoroalkyl, difluoroalkyl and trifluoroalkyl, with trifluoromethyl and mono- and di-fluoroethyl being preferred. Trifluoromethyl and 2,2-difluoroethyl are especially preferred.

Examples of cycloalkyl residues containing 3 to 8 carbon atoms substituted by halogen include: 2-fluorocyclopentyl group, 2-chlorocyclopentyl group, 2-bromocyclopentyl group, 3-fluorocyclopentyl group. , 3-chlorocyclopentyl group, 3-bromocyclopentyl group, 2-fluorocyclohexyl group, 2-chlorocyclohexyl group, 2-bromocyclohexyl group, 3-fluorocyclohexyl group, 3-chlorocyclohexyl group, 3-bromocyclohexyl group, 4 -Fluorocyclohexyl group, 4-chlorocyclohexyl group, 4-bromocyclohexyl group, difluorocyclopentyl group, dichlorocyclopentyl group, dibromocyclopentyl group, difluorocyclohexyl group, dichlorocyclohexyl group, dibromocyclohexyl group, trifluorocyclohexyl group, trifluorocyclohexyl group , Trichlorocyclohexyl group, tribromocyclohexyl group and the like.

Examples of hydroxy-substituted alkyl residues include the above alkyl residues containing 1-3 hydroxyl residues, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and the like. Hydroxymethyl is preferred.

Examples of oxo-substituted alkyl radicals are the abovementioned alkyl radicals or alkanoyl radicals, in which at least one carbon atom has been replaced by an oxo radical which forms a carbonyl group [-(C=O)-] in the alkyl chain. Alkyl-(C=O)-)], such as C ₁ -C ₆ alkanoyl, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and the like. Carbonyl group [- (C = O) - ] or an acetyl group, for example [- (C = O) -CH 3] or [- (C = O) -CH 2 -] form oxo substituted alkyl residue of preferable.

Examples of alkoxy-substituted alkyl residues include, for example, the above alkyl residues containing 1 to 3 alkoxy residues defined below, such as methoxymethyl, ethoxymethyl, 2-methoxyethylene, and the like.

Examples of acyl-substituted alkyl residues include the above alkyl residues containing 1-3 acyl residues defined below.

Examples of acyloxy-substituted alkyl residues include the above alkyl residues containing 1 to 3, preferably 1 acyloxy residue [-O-(C=O)-].

Examples of cycloalkyl substituted alkyl groups are the above alkyl residues containing 1 to 3, preferably 1 (optionally substituted) cycloalkyl groups, for example: cyclopropylmethyl, cyclobutylmethyl, cyclopentyl. Methyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 2- or 3-cyclopropylpropyl, 2- or 3-cyclobutylpropyl, 2- or 3- Examples thereof include cyclopentylpropyl, 2- or 3-cyclohexylpropyl. Cyclopropylmethyl and cyclohexylmethyl are preferred.

Examples of aryl-substituted alkyl groups include the above alkyl residues containing 1 to 3, preferably 1 (optionally substituted) aryl groups as defined below, such as phenylmethyl, 1- or 2-phenylethyl, 2- or 3-phenylpropyl and the like can be mentioned, and phenylmethyl, 1-phenylethyl, 2-phenylethyl and 2-phenylpropyl are preferable. Substituted aryl as defined below, especially 1 to 3, preferably 1 or 2, the same or different, preferably halogen (preferably F, Cl etc.), cyano, optionally substituted alkyl (preferably Methyl, ethyl, etc.), halogen-substituted alkyl (trifluoromethyl, etc.), optionally substituted alkoxy (methoxy, ethoxy, etc.), halogen-substituted alkoxy (difluoromethoxy, trifluoromethoxy, etc.), optionally substituted amino Groups (such as amino (NH ₂ —)) or mono- or di-alkylamino (preferably such as dimethylamino), optionally substituted heterocyclyl groups (such as pyrrolidinyl), alkyl-substituted piperazinyl, or morpholinyl, or especially R ¹ And/or a particularly preferred formula for R ^2.

Substituted by a phenyl substituted by a substituent selected from an optionally substituted heterocyclyl-sulfonyl group (such as N-morpholinyl-sulfonyl) forming an alkyl group substituted by a substituted aryl according to Alkyl groups are also particularly preferred.

Examples of heterocyclyl-substituted alkyl groups include the following, which may be substituted with 1 to 3, preferably 1 (optionally substituted), 1 to 3, preferably 1 substituent. Included are the above alkyl residues containing a defined heterocyclyl group. Preferably, the heterocyclyl group as the alkyl substituent is, for example, a morpholinyl group, a piperazinyl group, a piperidinyl group or the like. As defined above, the heterocyclyl group may be substituted and the preferred substituents are optionally substituted alkyl groups, preferably methyl or ethyl groups or trifluoromethyl groups. A piperidinyl group and a methyl-substituted morpholinyl group are particularly preferable.

Examples of heteroaryl-substituted alkyl groups include the above alkyl residues containing 1 to 3, preferably 1 (optionally substituted) heteroaryl groups as defined below, eg pyridinyl, pyridazinyl, pyrimidinyl. , Pyrazinyl, pyrazolyl, imidazolyl, benzimidazolyl, thiophenyl or oxazolyl groups such as pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, 2-pyridin-2-ylethyl, 2-pyridin-1-ylethyl, 2-pyridin-3-yl-ethyl, pyridazin-3-yl-methyl, pyrimidin-2-yl-methyl, pyrimidin-4-yl-methyl, pyrazol-2-ylmethyl, pyrazol-3-yl-methyl, pyrazole- 4-yl-methyl, pyrazol-5-ylmethyl, imidazol-2-ylmethyl, imidazol-5-yl-methyl, benzimidazol-2-yl-methyl, thiophen-2-yl-methyl, thiophen-3-yl-methyl , 1,3-oxazol-2-yl-methyl.

Optionally substituted pyridazinyl, such as especially pyridazin-3-ylmethyl and pyridazin-3-yl-ethyl, optionally substituted pyridinyl, such as optionally substituted pyridin-2-yl-methyl, pyridine- 3-yl-methyl, pyridin-4-yl-methyl, 2-pyridin-2-yl-ethyl, 2-pyridin-1-yl-ethyl, 2-pyridin-3-yl-ethyl, very particularly substituted Optionally pyridin-2-ylmethyl and 2-pyridin-2-ylethyl, optionally substituted pyrazol-3-yl-methyl, pyrazol-4-yl-methyl, pyrazol-5-yl-methyl, pyrazol-3- Alkyl groups substituted with yl-ethyl, pyrazol-4-yl-ethyl, pyrazol-5-yl-ethyl are preferred. Substituted pyridinyl-methyl such as substituted pyridinyl-methyl or substituted pyridinyl-ethyl in which 1, 2 or 3 substituents are selected from halogen (such as fluorine), C ₁ -C ₃ -alkyl (such as methyl and trifluoromethyl). Alkyl is particularly preferred. Fluorine-substituted pyridinyl-alkyl, such as fluorine-substituted pyridinyl-methyl or fluorine-substituted pyridinyl-ethyl, is particularly preferred. formula

Most preferred is fluorine-substituted pyridinyl-methyl according to.

Examples of heteroaryl-substituted alkyl groups further include cycloalkyl residues as defined above attached to a heteroaryl substituent by forming a fused ring with a heteroaryl substituent as defined above. , Preferably the fused cycloalkyl residue is cyclopentyl or cyclohexyl. Furthermore, preferably a fused heteroaryl substituent, for example, forms a fused 5- or 6-membered ring with Cycl, R ² or the group Cycl-[CQ] _n (wherein Q is C ₁ -C ₄ -alkyl). ) Is particularly preferred for the formula

Is pyridinyl, which forms a fused ring with, for example, cyclopenta-pyridinyl and cyclohexa-pyridinyl.

In each case, the heterocyclyl substituent of the alkyl residue as defined herein is 1 to 3, preferably 1 or 2, the same or different, preferably halogen (preferably F and Cl etc.), cyano Optionally substituted alkyl (such as methyl and ethyl), halogen-substituted alkyl (such as trifluoromethyl) and hydroxy-substituted alkyl (such as hydroxymethyl), optionally substituted alkoxy (preferably methoxy and ethoxy), An oxo group (═O), a heterocyclyl group defined below (such as an N-morpholinyl group), an aminocarbonyl group, an optionally substituted amino group (preferably amino (NH ₂ —)) or a mono- or di- It may be substituted with a substituent selected from -alkylamino (preferably dimethylamino and the like).

Examples of amino-substituted alkyl residues are the above-mentioned alkyl residues containing 1 to 3, preferably 1 (optionally substituted) amino groups as defined below, such as aminoalkyl (NH ₂ -Alkyl) or mono- or dialkylamino (eg aminomethyl, 2-aminoethyl, 2- or 3-aminopropyl, methylaminomethyl, methylaminoethyl, methylaminopropyl, 2-ethylaminomethyl, 3-ethylaminomethyl , 2-ethylaminoethyl, 3-ethylaminoethyl, etc.) or formula

Where R is an alkyl substituent as defined above, preferably a phenyl group, such groups being particularly preferred for R ^3.
And alkyl groups which may be substituted with an optionally substituted alkyloxycarbonylamino group.

Throughout the invention, optionally substituted substituted aryls preferably include:
For example, preferably 1 to 3 same or different hydroxy, halogen as defined above, cyano, optionally substituted amino as defined below, optionally substituted alkyl as defined above, Optionally substituted amino as defined below, optionally substituted alkyl as defined above, optionally substituted acyl as defined below, and optionally substituted as defined below. Good alkoxy, optionally substituted aryloxy as defined below, optionally substituted heterocyclyloxy, as defined below, optionally substituted aryl as defined herein, defined below 6-, which may be monocyclic or bicyclic, including phenyl, naphthyl, phenthenyl and anthracenyl optionally substituted by a substituent selected from optionally substituted heterocyclyl (e.g. designated as R< ⁶ >) An aromatic hydrocarbon residue containing 14 carbon atoms (excluding carbon atoms of possible substituents). Preference is given to optionally substituted phenyl, for example unsubstituted phenyl and phenyl substituted with 1 to 3, more preferably 1 or 2 identical or different substituents R ⁶ . 1 to 3 phenyl substituents (eg designated as R ⁶ ) are especially heterocyclyl as defined below, halogen as defined above eg F, optionally substituted amino as defined below. , such as in particular (-NH ₂₎ or mono - or Zia alkylamino (dimethylamino are preferred), cyano, alkoxy as defined below substituted, such as, in particular, di - fluoromethoxy and trifluoromethoxy, and in particular Basis

(* represents a binding site of a substituted phenyl substituent) and is selected from the group consisting of an optionally substituted sulfonyl group. Most preferred are halogen substituted phenyl, alkoxy substituted phenyl and hydroxyl substituted phenyl. The abovementioned substituents on phenyl are particularly preferred for the group "Cycl" in the formulas defined herein, the meaning of a substituted aryl group being a substituted phenyl.

Examples of alkyl-substituted aryl groups include the above aryls which are preferably substituted by straight or branched alkyl containing 1 to 8, preferably 1 to 4 carbon atoms as described above. Toluoyl is the preferred alkylaryl.

Examples of hydroxy-substituted aryl groups are preferably the above-mentioned aryls substituted by 1 to 3 hydroxyl residues, such as 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,4-di-. Examples thereof include hydroxyphenyl, 2,5-dihydroxyphenyl, 2,6-dihydroxyphenyl, 3,5-dihydroxyphenyl, 3,6-dihydroxyphenyl and 2,4,6-trihydroxyphenyl.

Examples of halogen-substituted aryl groups are the above aryls substituted by 1 to 3 halogen atoms, such as 2-chloro- or fluorophenyl, 3-chloro- or fluorophenyl, 4-chloro- or fluorophenyl, 2 ,4-di-(chloro and/or fluoro)phenyl, 2,5-di-(chloro and/or fluoro)phenyl, 2,6-di-(chloro and/or fluoro)phenyl, 3,5-di- (Chloro and/or fluoro)phenyl, 3,6-di-(chloro and/or fluoro)phenyl, 2,4,6-tri-(chloro and/or fluoro)phenyl and the like.

Examples of the alkoxy-substituted aryl group are preferably the above-mentioned aryls substituted with 1 to 3 of the following alkoxy residues, for example, preferably 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2- Included are ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2,4-di-methoxyphenyl and the like, as well as di-fluoromethoxyphenyl and trifluoromethoxyphenyl.

Throughout the invention, optionally substituted heterocyclyl preferably includes:
1 to 3, preferably 1 to 2 heteroatoms selected from the same or different N, O and S, preferably saturated or unsaturated, optionally substituted by 1 to 3 substituents Monocyclic or bicyclic 4- to 8-membered heterocyclic residue (see definition of possible substituents for optionally substituted heterocyclyl). Preferred are 4-, 5- and 6-membered saturated or unsaturated monocyclic or bicyclic optionally substituted heterocyclic residues, examples being azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, Piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl etc., for example azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-thiophene- 2-yl, tetrahydro-thiophen-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, morpholin-1-yl, morpholin-2-yl, morpholin-3-yl, piperidin- 1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran -4-yl and the like are included, and these may be condensed with an aromatic ring. Azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl residues are particularly preferred. The following optionally substituted heterocyclic residues as defined above are particularly preferred:
Particularly preferred for A ¹

(X is N, O or S, preferably S) and especially preferred for R ¹ and/or R ^2.

And particularly preferred as a substituent of an aryl group

Preferred substituents on the heterocyclyl residue include alkyl groups (preferably methyl and ethyl, etc.), hydroxyl groups, and oxo groups (=O).

Throughout the invention, optionally substituted heteroaryls include:
More preferably, it contains from 1 to 3 identical or different S, O, N series of heteroatoms in the ring and is therefore preferably a 5-12 membered heterocycle which may be monocyclic but may be bicyclic. Heteroaromatic hydrocarbon residues containing 4 to 9 membered ring carbon atoms forming an aromatic residue. Preferred aromatic heterocyclic residues include: pyridyl (pyridinyl), pyridyl-N-oxide, pyridazinyl, pyrimidyl, pyrazinyl, thienyl (thiophenyl), furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl. Or isoxazolyl, indoridinyl, indolyl, benzo[b]thienyl, benzo[b]furyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl, quinazolinyl, quinoxalinyl. For example, 5-membered heteroaryl such as thiazolyl (thiazol-2-yl, 2-thiazol-2-yl, 2-thiazol-4-yl, etc.), thienyl (thiophenyl) (thien-3-yl, etc.), pyrazolyl (1- Pyrazol-4-yl, 3-pyrazol-5-yl, etc., imidazolyl (imidazol-2-yl, 2-imidazol-4-yl, 1-imidazol-4-yl etc.), triazolyl (1-triazol-3-yl). 1,2-triazol-4-yl, etc., 1,2,4-triazol-3-yl or 1,2,3-triazol-4-yl), oxazolyl (2-oxazol-4-yl, 2-oxazole -5-yl), oxadiazolyl (1,2,4-oxadiazol-3-yl, etc.), and 6-membered heteroaryl such as pyridyl (pyridinyl) (pyrid-1-yl, pyrid-2-yl). , Pyrid-3-yl, pyrid-4-yl, 2-pyrid-4-yl, 2-pyrid-6-yl, 3-pyrid-5-yl (pyridin-1-yl, pyridin-2-yl, pyridine -3-yl, pyridin-4-yl, 2-pyridin-4-yl, 2-pyridin-6-yl, 3-pyridin-5-yl, etc.), pyrimidin-2-yl, pyrimidin-4-yl, pyrimidine -5-yl, and bicyclic heteroaromatic residues, especially benzimidazolyl (benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, etc.) and formulas

Benzimidazole-pyridinyl according to

5 or 6-membered heteroaromatic rings of the group of benzimidazoles which form fused rings with benzoxazol-2-yl or a heterocyclyl residue as defined above are preferred.

The heteroaryl group is one or more, preferably 1 to 3, more preferably 1 or 2 the same or different, especially halogen (preferably F and Cl etc.), cyano, a substitution as defined above. Optionally alkyl (preferably methyl, ethyl, n-propyl, i-propyl, etc.), halogen-substituted alkyl (difluoromethyl or trifluoromethyl, etc.), hydroxy-substituted alkyl (hydroxymethyl, etc.), aminocarbonyl-substituted alkyl ( Aminocarbonylmethyl etc.), carboxyl substituted alkyl (carboxylmethyl etc.), alkenyl group (propenyl etc.), optionally substituted alkoxy (preferably methoxy and ethoxy etc.), hydroxyl group (—OH), oxo group (═O) ), a carboxyl group [- (C = O) -OH ], such heterocyclyl groups (N- morpholinyl group as defined above), amino group _{(NH 2 - (C = O} ) - , etc.), substituted It may have a substituent selected from an amino group (preferably amino (NH ₂ —) etc.) or a mono- or di-alkylamino (preferably dimethylamino etc.).

In particular, examples of alkyl-substituted heteroaryl groups preferably include: by a linear or branched optionally substituted alkyl containing 1 to 8, preferably 1 to 4 carbon atoms as described above. Substituted above heteroaryl, such as especially methylimidazolyl (especially N-methylimidazolyl etc.), methylbenzimidazolyl (especially N-methylbenzimidazolyl, 5-methylbenzimidazolyl, 4-trifluoromethylbenzimidazolyl, 5-trifluoro) Methylbenzimidazolyl, N-aminocarbonylmethylbenzimidazolyl, etc.), N-carboxymethylaminocarbonyl, N-methylpyrazolyl, 1(N),5-dimethylpyrazolyl, methylpyridinyl (2-methylpyridin-3-yl, 2-methyl) Pyridin-4-yl, 3-methylpyridin-2-yl, 3-methylpyridin-3-yl, 3-methylpyridin-4-yl, 4-methylpyridin-2-yl, 5-methylpyridin-2-yl , 6-methylpyridin-2-yl), dimethylpyridinyl (3,5-dimethylpyridin-2-yl, 4,6-dimethylpyridin-3-yl, etc.), trifluoromethylpyridinyl, especially 3 -Or 4-trifluoromethylpyridin-2-yl, 6-trifluoromethylpyridin-3-yl, 3-hydroxymethylpyridin-2-yl, 5-methylpyrimidin-2-yl and the like.

Examples of halogen-substituted heteroaryl groups preferably include: especially fluoropyridinyl (eg 3-fluoro-pyridin-2-yl, 4-fluoro-pyridin-2-yl, 5-fluoro-pyridin- 2-yl, 6-fluoro-pyridin-2-yl, 3-chloro-pyridin-2-yl, 4-chloropyridin-2-yl, 5-chloro-pyridin-2-yl, 6-chloro-pyridin-2 -Yl, 2-fluoro-pyridin-3-yl, 4-fluoro-pyridin-3-yl, 5-fluoropyridin-3-yl, 6-fluoro-pyridin-3-yl, 2-chloro-pyridin-3- 4-chloro-pyridin-3-yl, 5-chloro-pyridin-3-yl, 6-chloro-pyridin-3-yl, 2-fluoro-pyridin-4-yl, 3-fluoro-pyridin-4-yl Yl, 5-fluoro-pyridin-4-yl, 6-fluoro-pyridin-4-yl, 2-chloropyridin-4-yl, 3-chloro-pyridin-4-yl, 5-chloro-pyridin-4-yl , 6-chloro-pyridin-4-yl), difluoropyridinyl (eg 3,5-difluoro-pyridin-2-yl), fluoro-chloro-pyridinyl (3-chloro-5-fluoro-pyridin-2). Heteroaryl, as defined above, which is substituted by 1 to 3, preferably 1 or 2, halogen atoms, such as F and/or Cl.

Examples of halogen- and alkyl-substituted heteroaryl groups preferably include: 1 to 3 halogen atoms, such as preferably F and/or Cl and 1 to 3 of the abovementioned straight-chain or branched groups. The above heteroaryl substituted by an optionally substituted alkyl residue, such as especially 3-fluoro-6-methylpyridin-2-yl, 3-chloro-5-trifluoromethylpyridin-2-yl.

Further preferred examples of substituted heteroaryl groups include:
Methoxypyridinyl (for example 3-, 4-, 5- or 6-methoxypyridin-2-yl, 2-, 4-, 5- or 6-methoxypyridin-3-yl, 2-, 3-, 5- Or 6-methoxypyridin-4-yl), hydroxypyridinyl (eg, 3-, 4-, 5- or 6-hydroxypyridin-2-yl, 2-, 4-, 5- or 6-hydroxypyridin-). 3-yl, 2-, 3-, 5- or 6-hydroxypyridin-4-yl etc.), oxopyridinyl (eg 6-oxo-1,6-dihydropyridin-2-yl, 2-oxo-1,2-dihydropyridine) -3-yl etc.), aminopyridinyl (6-dimethylaminopyridin-3-yl etc.), aminocarbonylpyridinyl (6-aminocarbonylpyridin-3-yl etc.), cyanopyridinyl (eg 3-, 4-, 5-). Or 6-cyanopyridin-2-yl, 2-, 4-, 5- or 6-cyanopyridin-3-yl, 2-, 3-, 5- or 6-cyanopyridin-4-yl, etc.), and 2 -Morpholin-4-yl-pyridin-4-yl.

As for the meaning of R ⁴ as 1 to 3, preferably 1 or 2 of the same or different substituents of the bicyclic heteroaryl group Het-2 according to any of the formulas defined herein, said hetero Aryl substituents are preferably halogen (preferably F and Cl etc.), cyano, optionally substituted alkyl as defined above (preferably methyl, ethyl, n-propyl, i-propyl etc.), halogen substituted Alkyl (such as difluoromethyl or trifluoromethyl), aminocarbonyl-substituted alkyl (such as aminocarbonylmethyl), carboxyl-substituted alkyl (such as carboxymethyl), optionally substituted alkoxy (preferably methoxy and ethoxy), and carboxyl group [ -(C=O)-OH]. R ⁴ is one or two same or different, F, Cl, cyano, optionally substituted alkyl (such as methyl and trifluoromethyl), aminocarbonyl-substituted alkyl (such as aminocarbonylmethyl), carboxyl-substituted alkyl ( It is most preferable to show a substituent selected from carboxymethyl, etc.), optionally substituted alkoxy (such as methoxy), and a carboxyl group [—(C═O)—OH].

With respect to the meaning of R ⁵ as 1-4, preferably 1-3, more preferably 1 or 2 same or different substituents of the heteroaryl group Cycl according to any of the formulas defined herein. , Said heteroaryl substituent is preferably halogen (preferably F and Cl etc.), cyano, optionally substituted alkyl as defined above (preferably methyl, ethyl, n-propyl, i-propyl etc.) , Halogen-substituted alkyl (such as difluoromethyl or trifluoromethyl), hydroxy-substituted alkyl (such as hydroxymethyl), optionally substituted alkoxy (such as methoxy and ethoxy), oxo group (═O), as defined above Heterocyclyl group (such as N-morpholinyl group), aminocarbonyl group (such as NH ₂ —(C═O)—), optionally substituted amino group (such as amino (NH ₂ —)) or mono- or It is selected from di-alkylamino, preferably dimethylamino and the like. R ⁵ is one or two same or different, F, Cl, cyano, optionally substituted alkyl (such as methyl, trifluoromethyl and hydroxymethyl), optionally substituted alkoxy (such as methoxy), For example, the expression

An oxo group (═O), a heterocyclyl group (such as an N-morpholinyl group), an aminocarbonyl group (such as NH ₂ —(C═O)—) that may form an oxo-substituted heteroaryl, or an optionally substituted amino group ( Most preferably, it represents a substituent selected from di-alkylamino such as dimethylamino).

The following and below optionally substituted acyls include: formyl (-CH(=O)), optionally substituted aliphatic acyl (alkanoyl=alkyl-CO(substituted for alkyl groups) Optionally referred to above definition of alkyl)), optionally substituted aromatic acyl (aroyl=aryl-CO-(see above definition of optionally substituted aryl for aryl group) Optionally)), optionally substituted heteroaromatic acyl (heteroaroyl=heteroaryl-CO- (can be referred to the above definition of optionally substituted heteroaryl for heteroaryl groups), or hetero Cyclic acyl (heterocycloyl=heterocyclyl-CO- (reference can be made to the above definition of optionally substituted heterocyclyl for a heterocyclyl group). Aliphatic acyl=alkanoyl=alkyl-CO- is preferred.

In amino which may be substituted according to the present invention include: amino (-NH _2), optionally substituted mono- or dialkylamino (alkyl -NH -, (alkyl) _{2 N} -) ( "alkyl Can refer to the definition of optionally substituted alkyl above). Optionally substituted mono- or diarylamino, mono- or diheteroarylamino and mono- or diheterocyclylamino groups or mixed type optionally substituted alkylarylamino, alkylheteroarylamino and alkylheterocyclylamino groups Are further included (reference can be made to the above definitions of optionally substituted alkyl, aryl, heteroaryl and heterocyclyl). According to the invention, the amino group further comprises the group -NH-.

The optionally substituted amino is preferably a mono- or optionally substituted, as described above, especially with 1 to 8, preferably 1 to 6, more preferably 1 to 3 carbon atoms. dialkylamino (alkyl -NH -, _(alkyl) 2 N-) is. The most preferred optionally substituted amino are mono- or dimethylamino and mono- or diethylamino. Amino group (-NH ₂₎ or (-NH-) and dimethylamino group is most preferred.

Throughout the present invention, optionally substituted alkanediyl is 1 to 3, preferably 1 or 2, halogen, hydroxy, oxo group (forming a carbonyl or acyl group) and amino group as defined above. May have a substituent selected from the group consisting of, preferably a divalent straight chain or branched chain having 1 to 7, preferably 1 to 6, and more preferably 1 to 4 carbon atoms. It is an alkanediyl group. The following may be mentioned as preferred examples: methylene, ethane-1,2-diyl, ethane-1,1-diyl, propane-1,3-diyl, propane-1,1-diyl, propane-1,2-. Diyl, propane-2,2-diyl, butane-1,4-diyl, butane-1,2-diyl, butane-1,3-diyl, butane-2,3-diyl, butane-1,1-diyl, Butane-2,2-diyl, butane-3,3-diyl, pentane-1,5-diyl and the like. Methylene, ethane-1,2-diyl, ethane-1,1-diyl, propane-1,3-diyl, propane-2,2-diyl and butane-2,2-diyl are particularly preferred. Most preferred are methylene and ethane-1,2-diyl.

Preferred substituted alkanediyl groups are hydroxy-substituted alkanediyl (such as hydroxy-substituted ethanediyl), oxo-substituted alkanediyl (such as oxo-substituted methylene or ethanediyl group) forming a carbonyl or acyl (acetyl) group, halogen-substituted alkanediyl group (F and An alkanediyl group substituted with one or two halogen atoms selected from Cl, preferably 2,2-difluoroethanediyl etc.), or an aminocarbonyl group such as the group [-(C=O)-NH- ] Is an alkanediyl group substituted with oxo and amino groups.

According to the invention, the substituents R ¹ and R ² or the respective groups —[CQ] _n — (wherein Q is C ₁ -C ₄ -alkyl) together with the nitrogen atom to which they are attached. To form an optionally substituted 3 to 6 membered ring that may contain additional heteroatoms. Wherein R ¹ and R ² (or the group —[CQ] _n — (wherein Q is C ₁ -C ₄ -alkyl)) are preferably together with the nitrogen atom to which they are attached. To form a 5- or 6-membered ring which may contain further heteroatoms selected from N and O, preferably one further heteroatom. Wherein R ¹ and R ² (or the group —[CQ] _n — (wherein Q is C ₁ -C ₄ -alkyl)) together with the nitrogen atom to which they are attached. It is most preferred to form a 6-membered ring that does not contain an additional heteroatom, forming an N-piperidinyl ring, or a 6-membered ring that contains one additional heteroatom O, that forms an N-morpholinyl ring. In particular, such N-piperidinyl rings are of the formula

May be substituted with an aryl or heteroaryl as defined above, preferably phenyl or piperidinyl, forming a bicyclic ring according to

According to the invention, A ¹ having the meaning of a straight-chain or branched alkanediyl group as defined above and R ³ having the meaning of an optionally substituted alkyl group as defined above are bound to these. Together with the nitrogen atom that has

(X is N, O or S, preferably S) (where

Is preferred)
It is further possible to form an optionally substituted 4 to 6 membered aliphatic monocyclic or bicyclic ring, optionally substituted with 1 to 3 substituents as defined above Is.

It is further possible in the context of the present invention that R ³ and A ² together with the nitrogen atom to which they are attached form an optionally substituted 4 to 7 membered ring, wherein The optional substituents are preferably selected from the heteroaryl and oxo groups defined above. In that case, the heteroaryl substituent, together with the nitrogen atom to which R ³ and A ² are attached, may also form a fused ring with the 4-7 membered ring formed by R ³ and A ² . .. Examples include residues according to the formula:

In a further aspect, the present invention provides novel compounds of general formula (I)

(In the formula,
R ¹ and R ² are the same or different,
-Hydrogen,
-Optionally substituted alkyl,
-Optionally substituted aryl,
-Optionally substituted heteroaryl,
—Independently selected from the group consisting of optionally substituted heterocyclyl, or —R ¹ and R ² together with the nitrogen atom to which they are attached may contain further heteroatoms. Forming an optionally substituted 3- to 6-membered ring;
X ¹ is O or S,
Y ¹ is hydrogen, optionally substituted alkyl or halogen,
Preferably hydrogen or C ₁ -C ₃ -alkyl, preferably hydrogen or methyl;
A ¹ is an optionally substituted alkanediyl;
A ² is an optionally substituted alkanediyl,
- a direct bond or - a sulfonyl group _(-SO 2 -)
And
R ³ is —hydrogen, or —optionally substituted alkyl; or A ¹ and R ³ together with the nitrogen atom to which they are attached are optionally substituted 4 to 6 members. A membered monocyclic or bicyclic ring; or R ³ and A ² together with the nitrogen atom to which they are attached form an optionally substituted 4-7 membered ring. ;
Ar is-an optionally substituted aryl,
-Optionally substituted monocyclic heteroaryl, or -substituent which, together with the nitrogen atom to which R ³ and A ² are attached, can be fused with the ring formed by R ³ and A ² . Which is optionally bicyclic heteroaryl)
Or, it relates to a pharmaceutically acceptable salt thereof.

It is particularly preferred if the substituents of formula (I) above have the following meanings:
R ¹ and R ² are the same or different,
-Hydrogen,
-Optionally substituted alkyl,
Independently selected from the group consisting of, or —R ¹ and R ² together with the nitrogen atom to which they are attached may contain further heteroatoms, optionally substituted 3 Form a 6-membered ring;
X ¹ is O or S;
Y ¹ is hydrogen or C ₁ -C ₃ -alkyl, such as preferably hydrogen or methyl;
A ¹ is an optionally substituted alkanediyl;
A ² is-an optionally substituted alkanediyl, or-a direct bond;
R ³ is —hydrogen, or —C ₁ -C ₃ -alkyl; or A ¹ and R ³ together with the nitrogen atom to which they are attached are optionally substituted 4-membered monocycles. Forming a formula ring; or R ³ and A ² together with the nitrogen atom to which they are attached form an optionally substituted 4-7 membered ring;
Ar is a bicyclic heteroaryl which may be substituted.

Preferred embodiment:
Embodiment A-2:
A further preferred embodiment of the present invention is a novel compound according to formula (A-II)

^{(Wherein, Cycl, Q, R 1,} X 1, X 2, X 3, X 4, R 3, A 1, A 2, R 4 and n are defined above for formula (A-I) Has meaning)
Or, it relates to a pharmaceutically acceptable salt thereof.

Embodiment A-3:
A further preferred embodiment of the present invention relates to the novel compounds according to formulas (AI) and (A-II) as defined above, wherein Cycl is a substituted or unsubstituted heteroaryl as defined above. Therein, heteroaryl is defined as 1 to 4, preferably 1 to 3, more preferably 1 or 2 and has the formula (A-IIIa) (A-IIIb), (A- IVa), (A-IVb), (A-IVc) and (A-IVd) may be substituted with a substituent R ⁵ as defined below in connection with the compound.

Embodiments A-3a and A-3b:
In a further preferred embodiment of the invention, Cycl is a compound according to formula (A-IIIa) or (A-IIIb), respectively.

^{(Wherein, Q, R 1, X 1} , X 2, X 3, X 4, R 3, A 1, A 2, Y 2, R 4 and n have the formula (A-I) or (A-II) Has the meaning defined above for
R ⁵ is 1 to 4, preferably 1 to 3, and more preferably 1 or 2,
-Halogen, preferably F and Cl,
-Optionally substituted alkyl, preferably methyl, trifluoromethyl, hydroxymethyl,
-Hydroxy,
-Alkoxy, preferably methoxy,
-Expression

An oxo group (=O) forming a substituted pyridinyl group of
- amino group, for example -NH _2, mono - or dialkylamino, preferably dialkylamino - an amino group, preferably _{NH 2 - (C = O)} -,
-Cyano, and -represents an optional substituent which may be independently selected from the group consisting of a heterocyclyl group, preferably a morpholinyl group)
A novel compound according to formulas (AI) and (A-II) as defined above, which is a substituted or unsubstituted heteroaryl selected from substituted or unsubstituted pyridinyl, which forms Related to salt.

Embodiments A-4a and A-4b:
Further preferred embodiments of the present invention are novel compounds according to formulas (A-IVa) and (A-IVb):

^{(Wherein, Q, R 1, X 1} , X 2, X 3, X 4, R 3, A 1, A 2, Y 2, R 4 and n have the formula (A-I), (A -II ) Or (A-IIIa) and (A-IIIb) have the meanings defined above,
R ⁵ has the meaning defined above for formulas (A-IIIa) and (A-IIIb), respectively)
Or, it relates to a pharmaceutically acceptable salt thereof.

In any of the formulas (A-IIIa), (A-IIIb), (A-IVa) or (A-IVb), R ⁵ represents 1 to 3, more preferably 1 or 2 substituents. Especially preferred is a substituent which may independently have one of the meanings defined above.

Embodiments A-4c and A-4d:
A further preferred embodiment of the present invention are the compounds according to formulas (A-IVc) and (A-IVd), each having one R ⁵ :

^{(Wherein, Q, R 1, X 1} , X 2, X 3, X 4, R 3, A 1, A 2, Y 2, R 4 and n have the formula (A-I), (A -II ), (A-IIIa), (A-IIIb), (A-IVa) and (A-IVb) have the meanings defined above.
R ⁵ has the meanings defined above for formulas (A-IIIa), (A-IIIb), (A-IVa) and (A-IVb), respectively)
A novel compound according to formula (A-IIIa), (A-IIIb), (A-IVa) or (A-IVb) or a pharmaceutically acceptable salt thereof, wherein

Preferably, in any of the above embodiments, the one or more substituents R ⁵ - halogen, preferably F and Cl,
-Optionally substituted alkyl, preferably methyl, trifluoromethyl, hydroxymethyl,
Independently selected from the group consisting of -hydroxy, and -alkoxy, preferably methoxy.

More preferably, in any of the above embodiments, the one or more substituents R ⁵ - halogen, preferably F and Cl, and - alkyl substituted, preferably methyl, trifluoromethyl, Independently selected from the group consisting of hydroxymethyl.

Even more preferably, in any of the above embodiments, the one or more substituents R ⁵ - halogen, preferably F and Cl
Independently selected from the group consisting of and most preferably F.

Embodiment A-5:
In a further preferred embodiment of the present invention, Cycl is 1 to 3, preferably 1 or 2, -hydroxy,
-Halogen, preferably F and Cl, preferably F,
-Cyano,
-Optionally substituted alkyl,
- amino optionally substituted, for example, (-NH ₂₎ or mono - or dialkylamino, preferably dimethylamino,
-An optionally substituted acyl,
Optionally substituted alkoxy, preferably methoxy, di-fluoromethoxy and trifluoromethoxy,
-Optionally substituted aryloxy,
-Optionally substituted heterocyclyloxy,
Optionally substituted aryl, and optionally substituted heterocyclyl, preferably optionally substituted pyrrolininyl, morpholinyl and piperazinyl,
An optionally substituted sulfonyl group, for example preferably of the formula

A substituent selected from the group consisting of heterocyclyl-substituted sulfonyl,
For example, preferably 1 to 3, preferably 1 or 2 substituents R as defined above in connection with the compounds according to any of formulas (A-Va) and (A-Vb) ⁶
And a pharmaceutically acceptable salt thereof according to formulas (AI) and (A-II) as defined above, which is a substituted aryl as defined above.

Embodiments A-5a and A-5b:
In a further preferred embodiment of the invention, Cycl is of formula (A-Va) or (A-Vb), respectively.

^{(Wherein, Q, R 1, X 1} , X 2, X 3, X 4, R 3, A 1, A 2, Y 2, R 4 and n have the formula (A-I) and (A-II) Has the meaning defined above for
R ⁶ has the meaning defined above, in particular 1 to 3, preferably 1 or 2, more preferably 1 -hydroxy,
-Halogen, preferably F and Cl, preferably F,
-Cyano,
-Optionally substituted alkyl,
- amino optionally substituted, for example, (-NH ₂₎ or mono - or dialkylamino, preferably dimethylamino,
-An optionally substituted acyl,
Optionally substituted alkoxy, preferably methoxy, di-fluoromethoxy and trifluoromethoxy,
-Optionally substituted aryloxy,
-Optionally substituted heterocyclyloxy,
Optionally substituted aryl, and optionally substituted heterocyclyl, preferably optionally substituted pyrrolininyl, morpholinyl and piperazinyl,
An optionally substituted sulfonyl group, such as preferably heterocyclyl-substituted sulfonyl, preferably of the formula

Represents a substituent selected from the group consisting of heterocyclyl-substituted sulfonyl)
According to formula (A-I) and (A-II) as defined above, which is a substituted aryl selected from substituted phenyls, forming a compound according to.

More preferably R ⁶ has the meaning of 1 or 2 substituents, preferably R ⁶ is 1-hydroxy,
-Halogen, preferably F and Cl, preferably F,
-Cyano,
-Optionally substituted alkyl,
- amino optionally substituted, for example, (-NH ₂₎ or mono - or dialkylamino, preferably dimethylamino,
Optionally substituted alkoxy, preferably methoxy, di-fluoromethoxy and trifluoromethoxy,
Optionally substituted heterocyclyl, preferably optionally substituted pyrrolininyl, morpholinyl and piperazinyl, and optionally substituted sulphonyl group, for example preferably heterocyclyl-substituted sulphonyl, preferably of the formula

Represents a substituent selected from the group consisting of heterocyclyl-substituted sulfonyl.

Even more preferably, R ⁶ is one -halogen, preferably F and Cl, preferably F,
-Cyano,
- amino optionally substituted, for example, (-NH ₂₎ or mono - or dialkylamino, preferably dimethylamino,
Optionally substituted alkoxy, preferably methoxy, di-fluoromethoxy and trifluoromethoxy,
Optionally substituted heterocyclyl, preferably optionally substituted pyrrolininyl, morpholinyl and piperazinyl, and optionally substituted sulphonyl group, for example preferably heterocyclyl-substituted sulphonyl, preferably of the formula

Represents a substituent selected from the group consisting of heterocyclyl-substituted sulfonyl.

Further embodiment A-6:
Further preferred embodiments of the present invention are according to any one of the above embodiments or as defined above or according to formulas (AI), (A-II), (A-IIIa), (A-IIIb), A novel compound according to any one of (A-IVa), (A-IVb), (A-IVc), (A-IVd), (A-Va) and (A-Vb) or a pharmaceutically acceptable compound thereof Regarding salt:
Embodiment (A-6a):
X ¹ is N,
There is one or two additional heteroatoms X (X ² , X ³ , X ⁴ )
X ² is C or N;
X ³ is C, N, S or O;
X ⁴ is C or N,
Basis

(In the formula, * indicates a binding site with an aminocarbonyl group, and ** indicates a binding site with an A ¹ -group)
To form
Provided that in the case of two additional heteroatoms, both are selected to be N, or one is N and one (except X ² ) is O;
X ³ and X ⁴ having the meaning of C or N may carry further substituents, for example preferably hydrogen (X ⁴ ═C) or a substituent as defined above for a substituted heteroaryl.

Embodiment (A-6b):
X ¹ is N,
X ² is C;
X ³ is O;
X ⁴ is C or N,
Basis

For example, preferably

(Embodiment (A-6b-1)
Or base

(Embodiment (A-6b-2)
(In the formula, * indicates a binding site with an aminocarbonyl group, and ** indicates a binding site with an A ¹ -group)
To form;
X ⁴ (which is C or N) may have further substituents, for example preferably hydrogen (where X ⁴ =C) or a substituent as defined above for a substituted heteroaryl.

Embodiment (A-6c):
X ¹ is N,
X ² is C;
X ³ is S;
X ⁴ is C or N, preferably C,
Basis

(In the formula, * indicates a binding site with an aminocarbonyl group, and ** indicates a binding site with an A ¹ -group)
To form;
X ⁴ may have further substituents, for example preferably hydrogen (X ⁴ ═C) or a substituent as defined above for a substituted heteroaryl.

Embodiment (A-6d):
X ² and X ³ are both N,
Basis

(In the formula, * indicates a binding site with an aminocarbonyl group, and ** indicates a binding site with an A ¹ -group)
To form;
X ¹ and X ⁴ are C;
X ¹ and/or X ⁴ may independently carry hydrogen or further substituents, eg substituents preferably as defined above for substituted heteroaryl.

Embodiment (A-6e):
X ¹ is C,
X ² , X ³ and X ⁴ are N,
Basis

(In the formula, * indicates a binding site with an aminocarbonyl group, and ** indicates a binding site with an A ¹ -group)
To form;
X ¹ may have hydrogen or further substituents, for example preferably the substituents defined above for substituted heteroaryl.

Embodiment (A-6f):
X ¹ , X ² and X ⁴ are N,
X ³ is C,
Basis

(In the formula, * indicates a binding site with an aminocarbonyl group, and ** indicates a binding site with an A ¹ -group)
To form;
X ³ may have hydrogen or further substituents, such as those defined above for substituted heteroaryl.

Embodiment (A-6g):
X ¹ is O,
X ² is C,
X ³ is N,
X ⁴ is C,
Basis

(In the formula,
Y ¹ represents -hydrogen or an optional substituent to -X ⁴ .
* Indicates a binding site with an aminocarbonyl group, and ** indicates a binding site with an A1-group)
To form.

Embodiment (A-6h):
X ¹ is S,
X ² is C,
X ³ is N,
X ⁴ is C,
Basis

(In the formula,
Y ¹ represents -hydrogen or an optional substituent to -X ⁴ .
* Indicates a binding site with an aminocarbonyl group, and ** indicates a binding site with an A1-group)
To form.

In any of the embodiments described herein, any additional substituents for X ¹ , X ³ and X ⁴ are also designated as Y ¹ or used in the substituent Y ¹ as used herein. Is equivalent to
- halogen, preferably Cl and F, more preferably Cl, and - optionally substituted alkyl, for example optionally substituted with 1 to 3 halogens or a methylene group linear or branched C ₁ -C ₃ -Alkyl; preferably methyl group, isopropyl group, CF ₃ group or methylene-substituted ethyl group

(In the formula, * indicates a binding site)
Is selected from the group consisting of.

Further preferred embodiments based on the above embodiments A-6g and A-6h:
More preferred embodiment 2a:
A further preferred embodiment of the invention is the compound according to formula (IIa):

Where R ¹ , R ² , Y ¹ , R ³ , A ¹ , A ² and Ar have the meanings defined above.
Embodiments A-6g above, wherein X is O, and a novel compound according to formula (I) as defined above, or a pharmaceutically acceptable salt thereof, which forms

Further embodiment 2b:
A further preferred embodiment of the invention is a compound according to formula (IIb):

Where R ¹ , R ² , Y ¹ , R ³ , A ¹ , A ² and Ar are defined above for Formula (I) and are associated with any one of the embodiments described herein. Has the meaning defined by
Embodiments A-6h above, wherein X is S, and a novel compound according to formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

Further embodiment 3:
In a further preferred embodiment of the invention at least one of R ¹ and R ² is of formula (III):

A straight chain alkyl group as defined above substituted with a cyclic group "Cycl" called R2 ^* , which forms a compound according to
"Cycl" is -an optionally substituted aryl as defined above,
-Optionally substituted heteroaryl as defined above, and-optionally substituted heterocyclyl as defined above,
Preferably selected from optionally substituted aryl or heteroaryl as defined above,
n is an integer of 1-8, preferably 1-4, preferably 1-3, for example 1, 2 or 3, more preferably 1.
The rest of R ¹ or R ² (called R ^{1 *} ) is-hydrogen,
-Optionally substituted alkyl as defined above,
Preferably selected from hydrogen and optionally substituted alkyl as defined above;
Implementations wherein X ¹ , Y ¹ , R ³ , A ¹ , A ² and Ar have the meanings defined in formula (I) and defined in the context of any one of the embodiments described herein. Form A-6g and A-6h, any one of the compounds defined above as Embodiments 2a and 2b, or a pharmaceutically acceptable salt thereof.

Embodiment 3a:
Another particularly preferred embodiment (3a) of the present invention is the compound defined herein as embodiments A-6g and A-6h, embodiment 2a, embodiment 2b and embodiment 3, especially R ¹ and At least one of R ² has the formula (IIIa)

An optionally substituted aryl as defined above, forming a compound according to, for example optionally substituted with a cyclic group "Cycl", designated R ^{2 *} , selected from the optionally substituted phenyl group. Is a linear alkyl group defined by
n is an integer of 1 to 8, preferably 1 to 4, preferably 1 to 3, for example 1, 2 or 3, more preferably 1; 1 to 3 phenyl rings, preferably 1 to 2 phenyl rings Is optionally substituted with one of the substituents defined above, preferably the substituents on the phenyl ring are selected from halogen and hydroxy;
The remainder of R ¹ or R ² (referred to as R ^1* ) has the meaning defined above, especially as defined for formula (I) and as defined in connection with embodiment 3 above;
X ¹ , Y ¹ , R ³ , A ¹ , A ² and Ar have the meanings defined in formula (I) and having the meanings defined in the context of any one of the embodiments described herein. A compound according to formula (III) or a pharmaceutically acceptable salt thereof.

Embodiment 3b:
Another preferred embodiment (3b) of the present invention is a compound defined herein as Embodiments A-6g and A-6h, Embodiment 2a, Embodiment 2b, Embodiment 3 and Embodiment 3a, in particular: At least one of R ¹ and R ² has the formula (IIIb)

An optionally substituted heterocyclic group, as defined above, which forms a compound according to, with a straight chain alkyl group, as defined above, substituted with a cyclic group "Cycl" which is "Het-1". Yes;
Het-1 is an optionally substituted, optionally fused, 5-membered or 6-membered heteroaryl, or-is an optionally substituted 5-membered or 6-membered as defined above. Selected from aliphatic heterocyclyl, preferably 6-membered aliphatic heterocyclyl,
The Het-1 group comprises one or two identical or different heteroatoms selected from N, O and S, preferably N and O, more preferably N;
1 to 3 Het-1 groups, preferably 1 or 2, preferably 1 as defined above, preferably halogen, cyano, optionally substituted alkyl as defined above, substituted Optionally alkoxy, hydroxyl group (-OH), oxo group (=O), carboxyl group [-(C=O)-OH], heterocyclyl group defined above, aminocarbonyl group, optionally substituted May have a substituent selected from good amino groups;
n is an integer of 1-8, preferably 1-4, preferably 1-3, for example 1, 2 or 3, more preferably 1.
The remainder of R ¹ or R ² (referred to as R ^{1 *} ) has the meanings defined above, in particular defined for formula (I) and defined in connection with embodiment 3 above,
X ¹ , Y ¹ , R ³ , A ¹ , A ² and Ar have the meanings defined in formula (I) and having the meanings defined in the context of any one of the embodiments described herein. A compound according to formula (III) or a pharmaceutically acceptable salt thereof.

Embodiment 3b-a:
In another preferred embodiment (3b-a) of the present invention, Het-1 has, for example, the formula (IIIb-a)

An optionally substituted 5 membered heteroaryl as defined above, preferably an optionally substituted pyrazolyl, forming a compound according to
R ⁵ is hydrogen or alkyl as defined above, preferably C ₁ -C ₃ -alkyl,
n is an integer of 1-8, preferably 1-4, preferably 1-3, for example 1, 2 or 3, more preferably 1.
The remainder of R ¹ or R ² (referred to as R ^{1 *} ) has the meaning defined above, in particular defined for formula (I) and having the meaning defined in connection with Embodiments 3 and 3b above, pyrazolyl The ring may have one or two further substituents as defined above;
Implementations wherein X ¹ , Y ¹ , R ³ , A ¹ , A ² and Ar have the meanings defined in formula (I) and defined in the context of any one of the embodiments described herein. Form 3b and compounds according to formula (IIIb) above or a pharmaceutically acceptable salt thereof.

Embodiment 3b-b:
In another preferred embodiment (3b-b) of the present invention, Het-1 has, for example, the formula (IIIb-b)

An optionally substituted 5-membered heteroaryl as defined above, preferably an optionally substituted imidazolyl, forming a compound according to
R ⁴ is hydrogen or alkyl as defined above, preferably C ₁ -C ₃ -alkyl,
n is an integer of 1-8, preferably 1-4, preferably 1-3, for example 1, 2 or 3, more preferably 1.
The remainder of R ¹ or R ² (referred to as R ^1* ) has the meanings defined above, in particular defined for formula (I) and having the meanings defined in connection with Embodiments 3 and 3b above, imidazolyl The ring may have one or two further substituents as defined above;
Implementations wherein X ¹ , Y ¹ , R ³ , A ¹ , A ² and Ar have the meanings defined in formula (I) and defined in the context of any one of the embodiments described herein. Form 3b and compounds according to formula (IIIb) above or a pharmaceutically acceptable salt thereof.

Embodiment 3b-c:
In another preferred embodiment (3b-c) of the present invention, Het-1 has, for example, the formula (IIIb-c)

An optionally substituted 6-membered heteroaryl as defined above, preferably an optionally substituted pyrimidinyl, forming a compound according to
n is 1-8, preferably 1-4, preferably 1-3, for example 1, 2 or 3, more preferably an integer of ¹ ; the rest of R ¹ or R ² (called R ^1* ) And having the meaning as defined for example, in particular for formula (I) and in the context of Embodiments 3 and 3b above, wherein the pyrimidinyl ring is 1-3, preferably 1 or 2 It may have a substituent as defined above;
Implementations wherein X ¹ , Y ¹ , R ³ , A ¹ , A ² and Ar have the meanings defined in formula (I) and defined in the context of any one of the embodiments described herein. Form 3b and compounds according to formula (IIIb) above or a pharmaceutically acceptable salt thereof.

Embodiment 3b-d:
In another preferred embodiment (3b-d) of the present invention, Het-1 has, for example, the formula (IIIb-d)

An optionally substituted 6-membered heteroaryl as defined above, preferably an optionally substituted pyridazinyl, forming a compound according to
n is 1-8, preferably 1-4, preferably 1-3, for example 1, 2 or 3, more preferably an integer of ¹ ; the rest of R ¹ or R ² (called R ^1* ) And having the meaning as defined for formula (I), especially as defined in connection with Embodiments 3 and 3b above, wherein the pyridazinyl ring is 1-3, preferably 1 or 2 It may have a substituent as defined above;
Implementations wherein X ¹ , Y ¹ , R ³ , A ¹ , A ² and Ar have the meanings defined in formula (I) and defined in the context of any one of the embodiments described herein. Form 3b and compounds according to formula (IIIb) above or a pharmaceutically acceptable salt thereof.

Embodiment 3b-e:
Another particularly preferred embodiment (3b-e) of the invention is Het-1 is of formula (IIIb-e)

Selected from an optionally substituted 6-membered heteroaryl as defined above, preferably an optionally substituted pyridinyl, forming a compound according to:
n is 1-8, preferably 1-4, preferably 1-3, for example 1, 2 or 3, more preferably an integer of ¹ ; the rest of R ¹ or R ² (called R ^1* ) And has the meaning as defined for formula (I), especially as defined in connection with Embodiments 3 and 3b above, wherein the pyridinyl ring is 1 to 3, preferably 1 or 2 It may have a substituent as defined above;
Implementations wherein X ¹ , Y ¹ , R ³ , A ¹ , A ² and Ar have the meanings defined in formula (I) and defined in the context of any one of the embodiments described herein. Form 3b and compounds according to formula (IIIb) above or a pharmaceutically acceptable salt thereof.

Embodiment 3b-f:
Another particularly preferred embodiment (3b-f) of the present invention is Het-1 is of formula (IIIb-f)

Selected from a substituted pyridinyl forming a compound according to
n is 1-8, preferably 1-4, preferably 1-3, for example 1, 2 or 3, more preferably an integer of ¹ ; the rest of R ¹ or R ² (called R ^1* ) And has the meaning as defined in relation to Embodiments 3 and 3b above, especially as defined for formula (I),
R ⁵ is 1 to 4, preferably 1 to 3, preferably 1 or 2, more preferably 1 -hydrogen-halogen, preferably Cl or F, more preferably F,
Optionally substituted alkyl, preferably C ₁ -C ₃ -alkyl, such as preferably methyl or trifluoromethyl,
Represents an optional substituent that may be independently selected from -hydroxy, and -alkoxy, preferably methoxy;
More preferably, R ⁵ is 1 to 3, preferably 1 or 2, and more preferably 1 -hydrogen,
-A halogen, preferably Cl or F, more preferably F, and-an optionally substituted alkyl, preferably a C ₁ -C ₃ -alkyl, for example preferably a substituent which may be independently selected from methyl or trifluoromethyl. Indicates;
Implementations wherein X ¹ , Y ¹ , R ³ , A ¹ , A ² and Ar have the meanings defined in formula (I) and defined in the context of any one of the embodiments described herein. Form 3b and compounds according to formula (IIIb) above or a pharmaceutically acceptable salt thereof.

Embodiment 3b-g:
Another particularly preferred embodiment (3b-g) of the present invention has the formula (IIIb-g)

Wherein n, R ¹ or the rest of R ² (referred to as R ^{1 *} ) has the meaning defined for embodiment 3b-f, R ⁵ is —halogen, preferably Cl or F, more preferably F,
Optionally substituted alkyl, preferably C ₁ -C ₃ -alkyl, such as preferably methyl or trifluoromethyl,
-Hydroxy,
Selected from alkoxy, preferably methoxy;
More preferably ^{R 5} is - halogen, preferably Cl or F, more preferably F, and -C ₁ -C ₃ - alkyl, for example, preferably selected from methyl or trifluoromethyl;
X< ¹ >, Y< ¹ >, R< ³ >, A< ¹ >, A< ² > and Ar are defined in formula (I) and in the context of any one of the embodiments described herein, in particular embodiment (IIIb-f). ) Has the meaning defined in the context of
Embodiment 3b and formula (IIIb), especially a compound according to Embodiment 3b-f and formula (IIIb-f) or a pharmaceutically acceptable salt thereof, forming a compound according to

Formulas (AI) and (I) and Embodiments A-2, A-3, A-3a, A-3b, A-4a, A-4b, A-4c, A-4d, A-5, A -5a, A-5b, A-6 and A-6a to A-6h and Embodiments 3, 3a, 3b, 3b-a, 3b-b, 3b-c, 3b-d, 3b-e, 3b-f. And very particularly preferably in the compounds defined by 3b-g, at least one of R ¹ and R ² is a linear, branched or cyclic alkyl group substituted by the cyclic group “Cycl”. Such linear, branched or cyclic alkyl group, the substituted cyclic group "Cycl", straight chain or branched alkyl group _{- [CQ] n - (Q} = H or _C 1 -C ₄ - alkyl) Means Particularly, when ^one of R ¹ and R ² is a branched alkyl group —[CQ] _n —(Q═C ₁ -C ₄ -alkyl), the alkyl group of Q is a condensed ring with a cyclic group “Cycl”. It is possible and preferred to form forms of cyclic alkyl residues. Thus, said "linear, branched or cyclic alkyl residue (which is substituted with the cyclic group "Cycl") is
-Preferably-methylene,
-Ethane-1,2-diyl,
-Ethane-1,1-diyl,
-Propane-1,3-diyl,
-Propane-1,1-diyl,
Optionally substituted linear or branched alkanediyl group as defined above, selected from -propane-1,2-diyl, and -propane-2,2-diyl; In form, preferably Cycl is selected from a cyclohexane and a cyclohexane, which may form a fused bicyclic ring, which is a Het-1 group selected from the 6-membered heteroaryls defined above. (Especially Q forms C ₁ -C ₄ -alkyl) optionally substituted cycloalkyl group.

More preferred are the optionally substituted linear or branched alkanediyl residues defined above. Even more preferably, such optionally substituted alkanediyl residues are methylene, ethane-1,2-diyl, ethane-1,1-diyl and propane-2,2-diyl; more preferably Selected from the group consisting of methylene or ethane-1,2-diyl; methylene is most preferred.

Embodiments A-2, A-3, A-3a, A-3b, A-4a, A-4b, A-4c, A-4d, A-5, A-5a, A-5b, A- 6 and A-6a to A-6h and each of Embodiments 3, 3a, 3b, 3b-a, 3b-b, 3b-c, 3b-d, 3b-e, 3b-f and 3b-g. The remainder of R ¹ or R ² , referred to as ^1* , X ¹ , Y ¹ , R ³ , A ¹ , A ² and Ar are defined in formula (AI) or (I) and described herein. It may have the meaning defined in the context of any one of the embodiments described above, in particular in relation to the embodiment 2 above and the following embodiments 4, 4a, 4b, 4c and 4d.

Further embodiment 4:
A further embodiment of the invention is that Ar is
Formula (IV)

An optionally substituted monocyclic or bicyclic heteroaryl, "Het-2", as defined above, which forms a compound according to
Het-2 is - together with the nitrogen atom to which members 5 may be substituted or defined above 6-membered monocyclic heteroaryl, and where -R ³ and A ² are attached, R ³ and Any one of the above defined compounds selected from the optionally substituted bicyclic heteroaryl defined above which is capable of being fused with the ring formed by A ² , especially for example Form A-6g and A-6h and further embodiment compounds or pharmaceutically acceptable salts thereof based thereon.

Embodiment 4a:
In another embodiment (4a), Ar, which is an optionally substituted monocyclic or bicyclic heteroaryl "Het-2", is of formula (IVa).

Selected from the optionally substituted 5 membered monocyclic heteroaryl forming a compound according to
X ⁵ is S or N—R ⁷ with R ⁷ having the meaning as defined above for R ⁵ , especially R ^{5 in} embodiments 3b-a and 3b-b, and is a 5-membered Het-2. A heteroaryl ring may have 1 to 3 additional substituents as defined above, preferably 1 or 2 additional substituents, more preferably 1 additional substituent as defined herein. To a compound such as especially embodiments A-6g and A-6h and compounds of further embodiments based thereon, especially a compound according to formula (IV) above or a pharmaceutically acceptable salt thereof.

Embodiment 4b:
In another embodiment (4b), Ar, which is an optionally substituted monocyclic or bicyclic heteroaryl "Het-2", has the formula (IVb), for example.

Selected from the optionally substituted 6-membered monocyclic heteroaryl forming a compound according to
Y ³ is C or N and the 6-membered heteroaryl ring of Het-2 has 1 to 3 substituents as defined above, preferably 1 or 2 substituents, more preferably 1 substituent. A compound as defined herein which may have a substituent, such as in particular embodiments A-6g and A-6h and compounds of further embodiments based thereon, especially a compound according to formula (IV) above or a pharmaceutically acceptable form thereof. Permissible salt.

Embodiment 4c:
In another embodiment (4c), Ar, which is an optionally substituted monocyclic or bicyclic heteroaryl "Het-2", has the formula (IVc), for example.

Selected from the optionally substituted bicyclic heteroaryl as defined above, forming a compound according to
-Both Y ² are C, or-one Y ² is N and one Y ² is C,
The bicyclic heteroaryl ring of Het-2 may have 1 to 3 substituents as defined above, preferably 1 or 2 substituents, more preferably 1 substituent. -2 optionally substituted bicyclic heteroaryl ring, together with the nitrogen atom to which R ³ and A ² are attached, can be fused with the ring formed by R ³ and A ² . A compound as defined herein, in particular embodiments A-6g and A-6h and compounds of further embodiments based thereon, especially a compound according to formula (IV) above or a pharmaceutically acceptable salt thereof. Regarding

Embodiment 4d:
In another embodiment (4d), Ar, which is an optionally substituted monocyclic or bicyclic heteroaryl "Het-2", has the formula (IVd)

Selected from optionally substituted bicyclic heteroaryl selected from benzimidazolyl as defined above, forming a compound according to
The benzimidazolyl ring of Het-2 may have 1 to 3 substituents as defined above, preferably 1 or 2 substituents, more preferably 1 substituent,
As defined herein, the benzimidazolyl ring of Het-2, together with the nitrogen atom to which R ³ and A ² are attached, can be fused with the ring formed by R ³ and A ² . Compounds of, for example, embodiments A-6g and A-6h and further embodiments based thereon, in particular compounds according to formulas (IV) and (IVc) above, or a pharmaceutically acceptable salt thereof.

In each of Embodiments 4, 4a, 4b, 4c and 4d above, the remaining substituents R ¹ , R ² , X ¹ , Y ¹ , R ³ , A ¹ and A ² are defined by formula (I). , As defined in connection with any one of the embodiments described herein, in particular defined by formula (I), above embodiment 2 as well as above embodiments 3, 3a, 3b, 3b-a. 3b-b, 3b-c, 3b-d, 3b-e, 3b-f and 3b-g may have the meaning defined in relation to them.

Further embodiments:
Further embodiment B-2a:
A particularly preferred embodiment (B-2a) is of formula (B-IIa)

(In the formula, 1 to 3 heteroatoms X (X ¹ , X ² , X ³ and/or X ⁴ ) are present, and X ^{1 to} X ⁴ may be the same or different, C, Independently selected from the group consisting of N, S and O)
Of compounds. Preferably, in formula (B-IIa), there are 1 to 3 heteroatoms X,
X ¹ is C, N, S or O;
X ² is C or N;
X ³ is C, N, S or O;
X ⁴ is C, N, S or O, preferably X ⁴ is C, N or S,
X ¹ , X ³ and X ⁴ having the meaning of C or N may have further substituents.

Embodiment B-2a-a:
Another particularly preferred embodiment (B-2a-a) is a compound of formula (B-IIa-a)

Where one or two additional heteroatoms X(X ² , X ³ , X ⁴ ) are present,
X ² is C or N;
X ³ is C, N, S or O;
X ⁴ is C or N,
Provided that in the case of two additional heteroatoms, both are selected from N, or one is N and one (except X ² ) is O;
X ³ and X ⁴ having the meaning of C or N may carry further substituents, eg preferably hydrogen or a substituent as defined above for a substituted heteroaryl).
To a compound according to formula (B-IIa) above, wherein X ¹ is N.

Embodiment B-2a-b:
Another particularly preferred embodiment (B-2a-b) is of formula (B-IIa-b)

(X ¹ and X ⁴ are C; X ¹ and/or X ⁴ may have hydrogen or a further substituent, for example preferably a substituent as defined above for a substituted heteroaryl).
A compound according to formula (B-IIa) above, wherein X ² and X ³ are both N.

Embodiment B-2a-c:
Another particularly preferred embodiment (B-2a-c) is of formula (B-IIa-c)

Where X ⁴ is C or N, preferably C, which may carry additional substituents, such as preferably hydrogen or a substituent as defined above for a substituted heteroaryl.
A compound according to formula (B-IIa) or (B-IIa-a) above, wherein X ¹ is N, X ² is C and X ³ is S, which form a compound of ..

Embodiment B-2a-d:
Another particularly preferred embodiment (B-2a-d) is of formula (IIa-d)

Wherein X ⁴ is C or N, which may optionally carry a further substituent, for example hydrogen or a substituent as defined above for the substituted heteroaryl.
To form a compound of
Formula (B-IIa-d-1)

(In the formula, C, X ⁴ may have hydrogen or an additional substituent, which is preferable.)
Or a compound of formula (B-IIa-d-2)

(In the formula, X ⁴ which is N may have an additional substituent)
To form a compound,
A compound according to formula (B-IIa) or (B-IIa-a) above, wherein X ¹ is N, X ² is C and X ³ is O.

Embodiment B-3b-e:
Another particularly preferred embodiment (B-3b-e) of the present invention has the formula (B-IIIb-e)

(In the formula, n is an integer of 1 to 8, preferably 1 to 4, preferably 1 to 3, for example 1, 2 or 3, and more preferably 1; the rest of R ¹ or R ² (R ^{1 *} and Referred to) has the meaning as defined in the above embodiments, especially as defined for formula (I), wherein the pyridinyl ring is 1 to 3, preferably 1 or 2 further substituents as defined above. May have;
R ³ , A ¹ , A ² and Ar have the meanings defined in the context of any one of the embodiments described herein, Z is of formula (AI)

Of embodiments A-6a, A-6b, A-6b-1, A-6b-2, A-6c, A-6d, A-6e, A-6f, A-6g and A-6h. Defined by any one, preferably formula (AI) and embodiments A-6a, A-6b, A-6b-1, A-6b-2, A-6c, A-6d. Has the meaning of a heterocyclic 5-membered ring)
According to the compound.

Embodiment B-3b-f:
Another particularly preferred embodiment (B-3b-f) of the present invention has the formula (B-IIIb-f)

(In the formula, n is an integer of 1 to 8, preferably 1 to 4, preferably 1 to 3, for example 1, 2 or 3, more preferably 1; the rest of R ¹ or R ² (R ^{1 *} and Has the meaning as defined in the above embodiments, especially as defined for formula (I),
R ⁵ is 1 to 4, preferably 1 to 3, preferably 1 or 2, more preferably 1 -halogen, preferably Cl or F, more preferably F,
Optionally substituted alkyl, preferably C ₁ -C ₃ -alkyl, such as preferably methyl or trifluoromethyl,
-Hydroxy,
-Indicates any substituent which may be independently selected from alkoxy, preferably methoxy;
Preferably ^{R 5} is - halogen, preferably Cl or F, more preferably F, and -C ₁ -C ₃ - alkyl, for example, preferably selected from methyl or trifluoromethyl;
R ³ , A ¹ , A ² and Ar have the meanings defined in the context of any one of the embodiments described herein, Z is of formula (AI)

Of embodiments A-6a, A-6b, A-6b-1, A-6b-2, A-6c, A-6d, A-6e, A-6f, A-6g and A-6h. Defined by any one, preferably formula (AI) and embodiments A-6a, A-6b, A-6b-1, A-6b-2, A-6c, A-6d. Has the meaning of a heterocyclic 5-membered ring)
According to the compound.

Embodiment B-3b-g:
Another very particularly preferred embodiment (B-3b-g) of the invention is of formula (B-IIIb-g)

Wherein n and the rest of R ¹ or R ² (designated R ^1* ) have the meanings defined for embodiment B-3b-f, R ⁵ is —halogen, preferably Cl or F, and Preferably F,
Optionally substituted alkyl, preferably C ₁ -C ₃ -alkyl, such as preferably methyl or trifluoromethyl,
-Hydroxy,
Selected from alkoxy, preferably methoxy;
More preferably ^{R 5} is - halogen, preferably Cl or F, more preferably F, and -C ₁ -C ₃ - alkyl, for example, preferably selected from methyl or trifluoromethyl;
R ³ , A ¹ , A ² and Ar have the meanings defined in the context of any one of the embodiments described herein, Z is of formula (AI)

Of embodiments A-6a, A-6b, A-6b-1, A-6b-2, A-6c, A-6d, A-6e, A-6f, A-6g and A-6h. Defined by any one, preferably formula (AI) and embodiments A-6a, A-6b, A-6b-1, A-6b-2, A-6c, A-6d. Has the meaning of a heterocyclic 5-membered ring)
According to the compound.

Embodiments A-2, A-3, A-3a, A-3b, A-4a, A-4b, A-4c, A-4d, A-5, A-5a, according to Formula (A-I). At least one of R ¹ and R ² in A-5b, A-6 and A-6a to A-6h and the compounds defined in embodiments B-3b-e, B-3b-f and B-3b-g. Tsugamoto _{- [CQ] n - (Q} = H or _C 1 -C ₄ - alkyl) linear substituted by a cyclic group "Cycl" including, branched or cyclic alkyl group, the resulting alkyl residue -Preferably-methylene,
-Ethane-1,2-diyl,
-Ethane-1,1-diyl,
-Propane-1,3-diyl,
-Propane-1,1-diyl,
Optionally substituted linear or branched alkanediyl group as defined above, selected from -propane-1,2-diyl, and -propane-2,2-diyl; In form, preferably Cycl is selected from -cyclopropane and -cyclohexane capable of forming a fused bicyclic ring, which is a 6-membered heteroaryl as defined above (in particular Q is C Very particular preference is given to optionally substituted cycloalkyl groups (forming _1- C ₄ -alkyl).

More preferred are the optionally substituted alkanediyl residues defined above. Even more preferably, such optionally substituted alkanediyl residues are methylene, ethane-1,2-diyl, ethane-1,1-diyl and propane-2,2-diyl; more preferably Selected from the group consisting of methylene or ethane-1,2-diyl; methylene is most preferred.

In each of the above embodiments B-3b-e, B-3b-f and B-3b-g, the remainder of R ¹ or R ² referred to as R ^{1 *} , Z, R ³ , A ¹ , A ² and Ar. May have the meaning defined in the context of any one of the embodiments described herein.

Embodiment B-4c:
Another particularly preferred embodiment (B-4c) is a compound as defined herein, especially-both Y ² are C, or-one Y ² is N and one Y ² is C. And
The bicyclic heteroaryl ring has from 1 to 3 substituents as defined above (eg as defined for R ⁴ above), preferably 1 or 2 substituents and more preferably 1 substituent. An optionally substituted bicyclic heteroaryl ring, together with the nitrogen atom to which R ³ and A ² are attached, is a ring formed by R ³ and A ² . Can be condensed,
Formula (B-IVc)

According to the compound.

Z is the formula (AI)

Of embodiments A-6a, A-6b, A-6b-1, A-6b-2, A-6c, A-6d, A-6e, A-6f, A-6g and A-6h. Defined by any one, preferably formula (AI) and embodiments A-6a, A-6b, A-6b-1, A-6b-2, A-6c, A-6d. Has the meaning of a heterocyclic 5-membered ring.

Embodiment B-4d:
Another very particularly preferred embodiment (B-4d) is a compound as defined herein, especially of formula (B-IVd)

Wherein the benzimidazolyl ring is 1 to 3 substituents as defined above (eg as defined above for R ⁴ ), preferably 1 or 2 substituents, more preferably 1 substituent. May have a substituent,
The benzimidazolyl ring, together with the nitrogen atom to which R ³ and A ² are attached, can be fused with the ring formed by R ³ and A ² ,
Z is the formula (AI)

Of embodiments A-6a, A-6b, A-6b-1, A-6b-2, A-6c, A-6d, A-6e, A-6f, A-6g and A-6h. Defined by any one, preferably formula (AI) and embodiments A-6a, A-6b, A-6b-1, A-6b-2, A-6c, A-6d. Has the meaning of a heterocyclic 5-membered ring)
According to (B-IVc) above, wherein the optionally substituted bicyclic heteroaryl as defined above which forms a compound according to is benzimidazolyl.

In each of the above embodiments B-4c and B-4d, the remaining substituents R ¹ , R ² , Z, R ³ , A ¹ and A ² are any of the embodiments described herein. In particular, embodiments B-2a, B-2a-a, B-2a-b, B-2a-c and B-2a-d and B-3b-e, B-3b-f, as defined in connection with one another. And B-3b-g may have the meaning defined in relation to B-3b-g.

Compounds according to the invention, such as in particular formulas (AI) and (I) and the above-mentioned embodiments A-2, A-3, A-3a, A-3b, A-4a, A-4b, A-4c, A-4d, A-5, A-5a, A-5b, A-6 and A-6a to A-6h and Embodiments 2, 3, 3a, 3b, 3b-a, 3b-b, 3b-c, 3b-d, 3b-e, 3b-f, 3b-g and 4, 4a, 4b, 4c and 4d and B-2a, B-2a-a, B-2a-b, B-2a-c, B-. 2a-d, B-3b-e, B-3b-f, B-3b-g, B-4c and B-4d, wherein A ¹ and A ² are each a substituted as defined above. Optionally selected alkanediyl, the same or different and optionally selected from -methylene and -ethane-1,2-diyl, or -A ¹ and R ³ are these An optionally substituted 4 to 6 membered monocyclic or bicyclic ring, preferably a 4 or 6 membered monocyclic or bicyclic ring, as defined above, together with a nitrogen atom to which it is attached. Very particular preference is given to forming a formula ring, more preferably a 4-membered ring. Among them, more preferably -A ¹ and A ² are the same and are methylene,
-A ¹ and A ² are the same and are ethane-1,2-diyl,
-A ¹ is methylene, A ² is ethane-1,2-diyl, -A ¹ is ethane-1,2-diyl, A ² is methylene,
-A ¹ and R ³ together with the nitrogen atom to which they are attached are an optionally substituted 4- to 6-membered aliphatic monocyclic or bicyclic ring, preferably a 4-membered ring. Forming, A ² is methylene, or -A ¹ and R ³ together with the nitrogen atom to which they are attached are optionally substituted 4 to 6 membered aliphatic monocyclic or Forms a bicyclic ring, preferably a 4-membered ring, A ² is ethane-1,2-diyl; more preferably -A ¹ and A ² are the same and are ethane-1,2-diyl. ,
-A ¹ is ethane-1,2-diyl, A ² is methylene, or -A ¹ and R ³ together with the nitrogen atom to which they are attached are optionally substituted. Form a 4-membered monocyclic ring, A ² is ethane-1,2-diyl; even more preferably -A ¹ and A ² are the same and are ethane-1,2-diyl, or A ¹ is ethane-1,2-diyl and A ² is methylene.

In a further preferred embodiment of the compounds according to the invention, the individual substituents in each case have the following definitions:
1. a) X ¹ has the meaning of O, X ³ has the meaning of N, X ² and X ⁴ have the meaning of C, and/or b) X ¹ has the meaning of N, X ³ has the meaning of O, X ² and X ⁴ have the meaning of C, and/or c) X ¹ has the meaning of N, X ³ has the meaning of S, X ² and X ⁴ has the meaning of C, and/or d) X ² and X ⁴ have the meaning of N, ^one of X ¹ and X ³ has the meaning of N, the rest have the meaning of C, and /Or e) X ¹ and X ⁴ have the meaning of N, X ² has the meaning of C and X ³ has the meaning of O;
Oxazolyl, thiazolyl, pyrazolyl as defined in embodiments A-6b, A-6b-1, A-6b-2, A-6c, A-6d, A-6e, A-6f, A-6g and A-6h. Heterocyclic five-membered rings selected from, triazolyl, oxadiazolyl and isoxazolyl and isothiazolyl are particularly preferred.

2. Y ¹ has the meaning of hydrogen, optionally substituted alkyl as defined above, preferably C ₁ , C ₂ or C ³ -alkyl as defined above, more preferably methyl.

3. 3. n is 1. 4. Q is H Cycle is the formula

(In the formula, * indicates a binding site)
It is the basis of

6. One of R ¹ and R ² is called R ^1* and is hydrogen, one of R ¹ or R ² is called R ^2* , hydrogen and optionally substituted alkyl as defined above, preferably Is selected from aryl-substituted alkyl and heteroaryl-substituted alkyl, where the aryl and heteroaryl substituents can each have 1 to 3 substituents as defined above. At least one optionally substituted aryl for R ¹ or R ^2, referred to as R 2 ^* - methyl or optionally substituted heteroaryl - particularly preferably a methyl, heteroaryl optionally substituted - Most preferred is methyl and substituted phenyl.

7. A ¹ and A ² are optionally substituted alkanediyl, the same or different,
-A ¹ and A ² are the same and are methylene,
-A ¹ and A ² are the same and are ethane-1,2-diyl,
-A ¹ is methylene and A ² is ethane-1,2-diyl,
-A ¹ is ethane-1,2-diyl, A ² is methylene,
-A ¹ and R ³ together with the nitrogen atom to which they are attached form an optionally substituted 4-membered monocyclic ring, A ² is methylene, or -A ¹ and R ³ together with the nitrogen atom to which they are attached form an optionally substituted 4-membered monocyclic ring, A ² is independently selected from ethane-1,2-diyl To be done.

A ¹ is methylene or ethane-1,2-diyl, A ² is ethane-1,2-diyl, or A ¹ and R ³ together with the nitrogen atom to which they are attached. Particularly preferably, it forms an optionally substituted 4-membered monocyclic ring, and A ² is ethane-1,2-diyl.

8. R ³ is hydrogen or optionally substituted alkyl as defined above, or A ¹ and R ³ together with the nitrogen atom to which they are attached are optionally substituted 4 membered members. It is preferably hydrogen, which forms a monocyclic ring.

9. Ar may be Het-1 as defined above, preferably optionally substituted monocyclic or bicyclic heteroaryl as defined above, preferably substituted as defined above. It is benzimidazolyl.

In a more preferred embodiment, R ¹ and R ² are different, one is hydrogen and the other is an optionally substituted alkyl. More preferably, ^one of R ¹ and R ² is hydrogen and the other is —an optionally substituted aryl group as defined above, preferably an optionally substituted phenyl group as defined above,
-An optionally substituted heteroaryl group as defined above, preferably-an optionally substituted pyridinyl group,
An optionally substituted pyridazinyl group,
An optionally substituted pyrimidinyl group,
An optionally substituted pyrazolyl group,
An alkyl residue substituted with an optionally substituted imidazolyl group.

Even more preferably, ^one of R ¹ and R ² is hydrogen and the other is an optionally substituted phenyl group,
An optionally substituted pyridinyl group,
An optionally substituted pyridazinyl group,
An alkyl residue substituted with an optionally substituted pyrimidinyl group,
Still more preferably, ^one of R ¹ and R ² is hydrogen and the other is —a optionally substituted phenyl group, preferably a substituted phenyl group as defined above, or —an optionally substituted pyridinyl group. Is an alkyl residue substituted with
Most preferred is an optionally substituted pyridinyl group as a substituent of an alkyl residue on ^one of R ¹ and R ² .

More preferably, a halogen-substituted pyridinyl group, such as a pyridinyl group, especially substituted with one fluorine substituent, such as especially the formula

A group is selected.

In an embodiment as defined above, Ar is a bicyclic heteroaryl, such as especially benzimidazole, especially the formula

It is further preferred to have the meaning of benzimidazol-2-yl according to

It is further preferred herein that A ¹ and A ² are each an optionally substituted alkanediyl as defined above, eg very particularly preferred that A ¹ and A ² are the same and methylene. , Or A ¹ and A ² are the same and are ethane-1,2-diyl, or A ¹ is methylene and A ² is ethane-1,2-diyl, or A ¹ is ethane-1. , 2-diyl, A ² is methylene, more preferably A ¹ and A ² are the same, ethane-1,2-diyl, or A ¹ is ethane-1,2-diyl. , A ² is methylene, or A ¹ and R ³ together with the nitrogen atom to which they are attached form an optionally substituted 4-membered monocyclic ring, A ² is ethane It is -1,2-diyl.

Particularly preferably, the compounds according to the invention are selected from the following compounds:

Or a pharmaceutically acceptable salt thereof.

A compound according to formula (A-II) wherein Cycl is an optionally substituted, optionally fused heteroaryl, eg Example Nos: 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 35, 36, 37, 38, 39, 40, 42, 43, 44, 45, 46, 47, 48, 49, 54, 55, 56, 57, 58, 59, 60, 61, 64, 76, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 108, 109, 110, 111, 112, 113, 114, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 131, 132, 134, 135, 136, 137, 138, 141, 142, 144, 145, 148, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 169, 170, 171, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 186, 187, 188, 189, 191, 192, 193, 194, 195, 196, 198, 199, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 218, 219, 220, 223, 226, 227, 228, 230, 231, 233, 236, 239, 242, 243, 244, 247, 249, 250, 251, 252, 253, 255, 256, 257, 258, 261, 264, 265, 266, 267, 268, 269, Nos. 270, 271, 272, 273, 274, 275, 276, 277, 278, 279 and 280 are more preferable.

Compounds according to formula (A-II) wherein Cycl is an optionally substituted, optionally fused 6-membered heteroaryl, eg Example Nos. 1, 2, 3, 4, 5, 6, 7, 8, 12, 35, 36, 37, 38, 39, 40, 42, 43, 44, 45, 46, 47, 48, 49, 54, 55, 56, 57, 58, 59, 61, 76, 79, 80, 81, 82, 83, 87, 89, 90, 92, 93, 94, 96, 97, 98, 99, 101, 102, 103, 104, 105, 106, 108, 109, 110, 111, 112, 113, 114, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 131, 132, 134, 135, 136, 137, 138, 141, 142, 144, 145, 148, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 169, 170, 171, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 186, 187, 188, 189, 191, 192, 193, 194, 195, 196, 198, 199, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 218, 219, 220, 223, 226, 227, 228, 230, 231, 233, 236, 239, 242, 243, 244, 247, 249, 250, 251, 252, 253, 255, 256, 257, 258, 261, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, No. 279 and No. 280 are more preferable.

A compound according to formula (A-II) wherein Cycl is an optionally substituted, optionally fused pyridinyl group, eg Example Nos. 1, 2, 3, 4, 5, 6, 7, 8, 12, 35, 36, 37, 38, 39, 40, 42, 43, 45, 47, 48, 49, 54, 55, 56, 57, 58, 59, 76, 79, 80, 81, 82, 83, 89, 90, 92, 94, 96, 97, 98, 99, 101, 102, 103, 104, 105, 106, 108, 109, 110, 111, 112, 113, 114, 116, 117, 118, 119, 120, 121, 123, 124, 125, 126, 127, 128, 131, 132, 134, 135, 136, 137, 138, 141, 142, 144, 145, 148, 150, 151, 152, 153, 154, 156, 157, 158, 159, 160, 162, 163, 164, 165, 166, 167, 169, 170, 171, 173, 176, 177, 179, 180, 181, 184, 186, 187, 189, 191, 192, 193, 194, 195, 196, 198, 199, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 218, 219, 220, 223, 226, 227, 228, 230, 231, 233, 236, 239, 242, 243, 247, 249, 250, 251, 252, 253, 255, 256, 257, 258, 264, 265, 266, 267, 268, 269, 272, 273, Nos. 274, 275, 276, 277, 278, 279 and 280 are more preferable.

A compound according to formula (A-II), wherein Cycl is an optionally fused, optionally fused pyridinyl group, having a 5-membered heterocycle according to (A-6-b) forming an oxazolyl ring, eg Example number:
126, 127, 128, 137, 141, 171, 173, 206, 207, 208, 223, 226, 227, 228, 230, 233, 236, 239, 247, 249, 250, 251, 252, 253, 255, 256, 257, 258, 264, 265, 266, 267, 268, 269, 272, 273;
And/or a compound according to formula (A-II) having a 5-membered heterocyclic ring according to (A-6-c) forming a thiazolyl ring, for example example number:
12, 35, 36, 37, 38, 39, 40, 42, 43, 45, 47, 54, 55, 56, 57, 58, 59, 76, 79, 80, 81, 82, 83, 89, 90, 94, 96, 97, 98, 99, 101, 102, 103, 104, 105, 106, 108, 110, 112, 113, 114, 116, 118, 119, 120, 121, 123, 124, 125, 134, 135, 148, 151, 152, 154, 157, 158, 159, 160, 163, 164, 165, 166, 176, 177, 179, 180, 184, 186, 189, 193, 194, 195, 196, 199, 209, 211, 212, 213, 214, 215, 218, 231, 242, 243, 274, 275, 276;
And/or a compound according to formula (A-II) having a 5-membered heterocyclic ring according to (A-6-g) and/or (A-6-h) forming an isoxazolyl or isothiazolyl ring, for example example number:
Nos. 1, 2, 3, 4, 5, 6, 7, 8 and 280;
And/or a compound according to formula (A-II) having a 5-membered heterocyclic ring according to (A-6-e) and/or (A-6-f) forming a triazolyl ring, eg Example No:
Nos. 169, 170, 181, and 277 are more preferable.

Further, a compound in which ^one of R ¹ and/or R ² is a fluorine-substituted pyridinyl group, for example, Example No.:
1, 2, 3, 4, 5, 6, 7, 8, 40, 94, 112, 113, 114, 118, 119, 120, 121, 125, 126, 127, 128, 134, 135, 148, 151, 152, 154, 157, 163, 164, 165, 166, 169, 176, 177, 179, 180, 181, 186, 193, 196, 199, 206, 208, 209, 211, 212, 213, 214, 218, 223, 226, 227, 228, 230, 231, 233, 239, 242, 243, 247, 249, 250, 251, 253, 255, 256, 257, 264, 265, 266, 267, 268, 269, 272, Nos. 273, 274, 275, 276, 277, 279 and 280 are preferred.

Pharmaceutically acceptable salts of the compounds according to the invention include, for example, salts with suitable anions, such as carboxylates, sulfonates, sulfates, chlorides, bromides, iodides, phosphates, tartrates, methane. Sulfonate, hydroxyethanesulfonate, glycinate, maleate, propionate, fumarate, toluenesulfonate, benzenesulfonate, trifluoroacetate, naphthalenedisulfonate-1,5, salicylic acid Included are salts, benzoates, lactates, salts of malic acid, salts of 3-hydroxy-2-naphthoic acid-2, citrates and acetates.

The pharmaceutically acceptable salts of the compounds according to the invention also include, for example, salts with suitable pharmaceutically acceptable bases, such as alkali or alkaline earth hydroxides (eg NaOH, KOH, Ca(OH)). ₂ , salts with Mg(OH) _2, etc., amine compounds (eg ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, ethanolamine, diethanolamine, triethanolamine, methylglucamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzyl) Amine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine, 2-amino-2-methylpropanol-(1), 2-amino-2-methylpropanediol-(1,3), 2-amino 2-hydroxyl-methyl-propanediol-(1,3) (TRIS) and the like).

Depending on their structure, the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers) in the presence of asymmetric carbon atoms. As such, the present invention includes the use of enantiomers or diastereomers and their respective mixtures. The pure enantiomeric forms may be obtained by conventional methods of optical resolution, for example by fractional crystallization of diastereomers by reaction with optically active compounds. Since the compounds according to the invention can occur in tautomeric forms, the present invention covers the use of all tautomeric forms.

The compounds provided by the present invention may exist as a mixture of various possible isomeric forms, in particular stereoisomers, for example E- and Z-, syn and anti and optical isomers. E- and Z-isomers as well as optical isomers and any mixtures of these isomers are claimed.

The novel compounds of the present invention may exist in amorphous, crystalline or partially crystalline form, or may exist as hydrates.

Surprisingly, it has been found that the novel compounds according to formula (A-I) as defined above and further embodiments thereof act as ferroportin inhibitors, thus their use as pharmaceuticals, for example as ferroportin inhibitors in particular. Suitable for use.

As already explained above, ferroportin is an iron transport protein, responsible for the uptake of free iron through the intestine and its movement into the blood circulation, thereby transporting iron to the appropriate tissues and organs. Inactivation or inhibition of ferroportin disables iron delivery, thereby reducing iron absorption in the intestine. Therefore, ferroportin inhibition within the meaning of the present invention includes inhibition of iron transport from cells into the blood circulation and inhibition of iron absorption in the intestine. In that, inhibition of iron transport and/or iron perfusion, for example, inhibition of ferroportin's iron transport activity, and thus inhibition of iron perfusion, triggering of ferroportin internalization, degradation and/or reduction, hepcidin agonists, ie hepcidin and It can be done by a variety of mechanisms including the administration of competing compounds or compounds that inhibit the binding of hepcidin to ferroportin.

Ferroportin inhibition can be measured by measuring inhibition of ferroportin-mediated iron transport activity in the iron response assay (BLAzer-Assay) described in more detail in the Examples below. Furthermore, by testing ferroportin internalization and/or degradation in a ferroportin internalization and degradation assay (FACS), as described in more detail in the Examples below, respectively, or testing ubiquitination and degradation of ferroportin. By doing so, ferroportin inhibition can be measured. In addition, ferroportin is determined by measuring its activity as a hepcidin agonist, for example by measuring the binding capacity of hepcidin to ferroportin in the hepcidin internalization assay (J774), as described in more detail in the Examples below. Inhibition can be measured. Furthermore, ferroportin inhibition is measured by confirming the inhibition of hepcidin binding to ferroportin in a biophysical ferroportin-hepcidin binding assay (Hep Bind FP), for example, as described in more detail in the Examples below. can do. Furthermore, by measuring the activity of a compound with respect to its ability to block iron delivery through ferroportin, using a test for measuring inhibition of iron efflux, for example as described in more detail in the Examples below. , Ferroportin inhibition can be measured.

Therefore, ferroportin inhibition in the sense of the present invention can be defined in particular by exhibiting ferroportin inhibitory activity in at least one of the above-mentioned test methods specifically indicated below:
Inhibition of ferroportin-mediated iron transport activity in iron response assay (blazer assay): IC ₅₀ value [μm] of 100 or less (≦100), preferably 50 or less (≦50), more preferably less than 50 (<50).

Ferroportin internalization and degradation assay (FACS): EC ₅₀ value [μm] of 100 or less (≦100), preferably 50 or less (≦50), more preferably less than 50 (<50).

Ferroportin ubiquitination and degradation: effects that are visually examined on Western blots of "+comparable to hepcidin", "+/- intermediate effect" and "+/+/- strong intermediate effect". “+” or “+/+/−” is preferable, and the effect “+” is most preferable.

Hepcidin internalization assay (J774): IC ₅₀ value of 100 or less (≦100), preferably 50 or less (≦50), more preferably less than 50 (<50).

Biophysical ferroportin-hepcidin binding assay: IC ₅₀ values of 100 or less (≦100), preferably 50 or less (≦50), more preferably less than 50 (<50).

Inhibition of iron efflux: IC ₅₀ values of 100 or less (≦100), preferably 50 or less (≦50), more preferably less than 50 (<50).

Ferroportin inhibition can be further measured in an in vivo model, as described in more detail in the Examples below. Suitable in vivo models include, for example, testing for hypoxemia in naive mice via measurement of serum iron reduction; testing for prevention of iron absorption in anemia rats via measurement of serum iron inhibition; measuring serum iron reduction. -Mediated test for correction of hyperironemia in β2-microglobulin deficient mice; test for prevention of iron overload in β2-microglobulin deficient mice via measurement of total iron in the spleen or liver; Can include testing for anemia, ineffective erythropoiesis and improvement in iron overload.

The activity of the compounds of the invention as ferroportin inhibitors can be measured, in particular, by the method described in the examples below.

Further, as already explained above, ferroportin inhibition can be carried out, for example, by hepcidin, an essential regulator of iron absorption, which inhibits ferroportin and thus blocks iron transport from the cell to the blood circulation and iron absorption. Even more surprisingly, it has been found that some of the compounds defined herein act as hepcidin mimetics or hepcidin agonists and are also involved in ferroportin inhibition within the meaning of the invention.

The compounds defined in the present invention are therefore also suitable for the inhibition of iron transport from the cells into the blood circulation and the inhibition of iron absorption in the intestine and for use as hepcidin mimetics or hepcidin agonists.

Due to the activity of the compounds defined herein as ferroportin inhibitors, the compounds of the present invention are used in the inhibition of iron transport mediated by ferroportin, thereby impairing iron metabolism resulting in elevated iron levels, iron. Prevention and/or diseases associated with elevated levels, increased iron absorption or iron overload, or diseases caused by elevated iron levels, increased iron absorption or iron excess, diseases associated with ineffective erythropoiesis, or decreased hepcidin levels Alternatively, it is particularly suitable for use in therapy. In addition, the compounds of the invention limit the amount of iron available to pathogenic microorganisms such as the bacterium Vibrio vulnificus, thereby preventing or treating infections caused by said pathogenic microorganisms. Suitable for use in adjunct therapy.

Among them, diseases associated with, caused by or resulting in elevated iron levels, increased iron absorption, iron overload (eg tissue iron overload) or ineffective erythropoiesis are thalassemia, aberrant hemoglobinosis. , Including hemoglobin E disease (HbE), hemoglobin H disease (HbH), hemochromatosis, hemolytic anemia, such as sickle cell anemia (sickle cell disease) and congenital dysplastic anemia.

Diseases associated with, caused by, or resulting in elevated iron levels, increased iron uptake, iron overload (eg, tissue iron overload) further include neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, The compounds are believed to be effective by limiting the deposition or increase of iron in tissues or cells.

The compounds of the present invention further include the prevention and/or treatment of excess iron or radicals caused by excess iron, formation of reactive oxygen species (ROS) and oxidative stress, as well as heart, liver and It is suitable for use in the prevention and/or treatment of endocrine damage as well as the prevention and/or treatment of excess iron or inflammation induced by iron overload.

Diseases with ineffective erythropoiesis include, among others, myelodysplastic syndrome (MDS, myelodysplasia) and polycythemia vera and congenital erythropoietic anemia.

Further diseases, disorders and/or disease states are genes involved in sensing systemic iron stores such as hepcidin (Hamp1), hemochromatosis protein (HFE), hemojuvelin (HJV) and transferrin receptor 2 (TFR2). Excess caused by mutations in, for example, diseases associated with HFE and HJV gene mutations in particular, chronic hemolysis-related diseases, sickle cell disease, erythrocyte membrane disorders, glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency) ), erythropoietic porphyria, Friedreich's ataxia and subgroups of iron overload, eg transfusional iron overload, iron poisoning, pulmonary thrombocythemia, osteopenia, insulin resistance, African iron overload, Hallerholden spats. Syndrome, hyperferritinemia, ceruloplasmin deficiency, neonatal hemochromatosis and erythropathy (including thalassemia (including α-thalassemia, β-thalassemia and δ-thalassemia, intermediate thalassemia), sickle cell disease and myelodysplastic syndrome) Including.

Additional diseases and/or disorders and/or disease states associated with elevated iron levels include, but are not limited to, ataxia, Friedreich's ataxia, age-related macular degeneration, age-related cataract, age-related retinal disease and nerves. Degenerative diseases such as those with elevated iron levels including pantothenate kinase-related neurodegeneration, restless leg syndrome and Huntington's disease are included.

The compounds of the invention are further suitable for use in the prevention and treatment of diseases caused by deficiency of hepcidin.

In light of this, a further object of the present invention is a medicament comprising one or more of the compounds as defined above, eg for the prophylaxis and treatment of any of the signs, conditions, disorders or diseases as defined above. For pharmaceuticals.

A further object of the invention is a medicament comprising one or more of the compounds according to the invention as defined above and optionally one or more pharmacologically acceptable carriers and/or auxiliary substances and/or solvents. Compositions and pharmaceuticals. A further object of the present invention relates to pharmaceutical compositions and medicaments which comprise one or more of the compounds of the invention defined above and optionally one or more further pharmaceutically active compounds. Said pharmaceutical composition comprises, for example, up to 99% by weight or up to 90% by weight or up to 80% by weight or up to 70% by weight of a compound of the invention, the remainder being the respective pharmaceutically acceptable carrier and/or adjuvant. Formed by the agent and/or the solvent and/or optionally the further pharmaceutically active compound.

Among them, pharmaceutically acceptable carriers, auxiliary substances or solvents include various organic or inorganic carriers and/or auxiliary substances commonly used for medicinal purposes, especially solid pharmaceutical preparations. A suitable pharmaceutical carrier, auxiliary substance or solvent. Examples include excipients (saccharose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc.); binders (cellulose, methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, acacia) , Polyethylene glycol, saccharose, starch, etc.); disintegrant (starch, hydrolyzed starch, carboxymethyl cellulose, carboxymethyl cellulose calcium salt, hydroxypropyl starch, sodium starch glycolate, sodium bicarbonate, calcium phosphate, calcium citrate, etc.); lubrication Agents (magnesium stearate, talc, sodium lauryl sulfate, etc.); Flavoring agents (citric acid, menthol, glycine, orange powder, etc.); Preservatives (sodium benzoate, sodium bisulfite, parabens (eg, methylparaben, ethylparaben, propyl) Parabens, butyl parabens, etc.); stabilizers (citric acid, sodium citrate, acetic acid and triplex(R) series polycarboxylic acids, such as diethylenetriaminepentaacetic acid (DTPA)); suspending agents (methylcellulose, polyvinyl Pyrrolidone, aluminum stearate and the like); Dispersant; Diluent (water, organic solvent and the like); Wax, fat and oil (beeswax, cocoa butter, etc.); Polyethylene glycol;

Liquid pharmaceutical formulations such as solutions, suspensions and gels typically include a liquid carrier such as water and/or a pharmaceutically acceptable organic solvent. Furthermore, such liquid formulations may contain, for example, pH adjusting agents, emulsifying or dispersing agents, buffers, preservatives, wetting agents, gelatinizing agents (eg methylcellulose), dyes and/or flavoring agents as defined above. It can also be included. The composition may be isotonic, ie it may have the same osmotic pressure as blood. The isotonicity of the composition may be adjusted by using sodium chloride and other pharmaceutically acceptable agents such as dextrose, maltose, boric acid, sodium tartrate, propylene glycol and other inorganic or organic soluble substances. You can The viscosity of the liquid composition can be adjusted with pharmaceutically acceptable thickening agents such as methyl cellulose. Other suitable thickeners include, for example, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer and the like. The preferred concentration of thickening agent depends on the agent selected.

Pharmaceutically acceptable preservatives can be used to extend the shelf life of liquid compositions. Benzyl alcohol may be suitable, although multiple preservatives may be used including, for example, paraben, thimerosal, chlorobutanol and benzalkonium chloride.

The pharmaceutical composition is suitable for, for example, intravenous, intraperitoneal, intramuscular, vaginal, buccal, transdermal, subcutaneous, mucosal skin, oral, rectal, transdermal, topical, intradermal, intragastric or intradermal application. For example, pills, tablets, enteric coated tablets, film tablets, layer tablets, sustained release preparations for oral, subcutaneous or dermal administration (particularly as plasters), depot preparations, dragees, suppositories, gel preparations, Salve, syrup, granule, suppository, emulsion, dispersion, microcapsule, microformulation, nanoformulation, liposome formulation, capsule, enteric-coated capsule, powder, inhalation powder, microcrystalline formulation, inhalation spray, dusting agent , Droplets, nose drops, nasal sprays, aerosols, ampoules, solutions, juices, suspensions, infusion solutions or injection solutions.

A further object of the present invention is one or more of the compounds defined above and at least one further pharmaceutically active compound, such as a compound especially for preventing and treating iron overload and related conditions, preferably Iron chelate compounds, or compounds for the prevention and treatment of any of the above defined conditions, disorders or diseases, such as thalassemia, hemochromatosis, neurodegenerative diseases (such as Alzheimer's disease or Parkinson's disease) and related conditions, among others. It relates to a pharmaceutical or combination preparation comprising a pharmaceutically active compound for prevention and treatment.

A further object of the present invention relates to the use of a compound as defined above in combination therapy (fixed dose or free dose combination for continuous use) with one or two other active ingredients (drugs). .. Such combination therapy involves co-administration of a compound of the invention with at least one additional pharmaceutically active compound (drug). Combination therapy with a fixed dose combination therapy involves co-administration of a compound of the invention with a fixed dose formulation and at least one additional pharmaceutically active compound. Combination therapy in free-dose combination therapy is the simultaneous administration of the individual compounds or the sequential use of the individual compounds distributed over a period of time, with the compounds of the invention in free dose of each compound and at least one additional pharmaceutical agent. And co-administration of the active compounds. The at least one further pharmaceutically active compound (drug) is, in particular, an agent that reduces iron overload (eg Tmprs6-ASO) or an iron chelator, especially curcumin, SSP-004184, deferitrin, deferasirox, deferoxamine. And/or deferiprone, or an antioxidant (such as n-acetylcysteine), an antidiabetic agent (such as a GLP-1 receptor agonist), an antibiotic (such as vancomycin (Van) or tobramycin), a therapeutic agent for malaria, an anticancer agent, an antifungal agent Drugs, therapeutic agents for neurodegenerative diseases (such as Alzheimer's disease and Parkinson's disease) (eg, dopamine agonists such as levodopa), antiviral agents (such as interferon α or ribavirin) or immunosuppressants (cyclosporin A or cyclosporin A derivatives), iron Includes supplements, vitamin supplements, erythropoiesis stimulants, anti-inflammatory biologics, antithrombotic agents, statins, pressors and inotropic compounds.

A further object of the present invention is to prevent and/or treat diseases caused by deficiency of hepcidin or disorders of iron metabolism, such as in particular iron overload conditions such as especially thalassemia and hemochromatosis and other disorders mentioned in the present application. To the use of the above combinations to

A further object of the present invention relates to the use of a compound as defined herein per se or a combination therapy as hereinbefore described in combination with blood transfusion.

The compounds, medicaments and/or combination preparations according to the invention can be administered orally, parenterally and intravenously.

For this purpose, the compounds according to the invention are preferably pills, tablets, such as enteric-coated tablets, film tablets and layer tablets, sustained-release preparations for oral administration, depot preparations, dragees, granules, emulsions, Dispersants, microcapsules, microformulations, nanoformulations, liposome preparations, capsules such as enteric coated capsules, powders, microcrystalline preparations, dusters, droplets, ampoules, solutions, suspensions, infusion solutions or injection solutions Or a pharmaceutical composition in the form of a formulation suitable for inhalation.

In a preferred embodiment of the invention the compound is administered in the form of tablets or capsules as defined above. They can be present, for example, in acid-resistant form or by means of a pH-dependent coating.

The compounds of the invention as active substances can be administered in unit doses of, for example, 0.001 mg/kg to 500 mg/kg of body weight, for example 1 to 4 times per day. However, the dose may be increased or decreased depending on the age, weight, condition of the patient, severity of the disease or type of administration.

Therefore, a further object of the invention is to prepare a medicament, especially for oral or parenteral administration, especially for the preparation of a medicament for the prevention and treatment of any of the signs, conditions, disorders or diseases defined above. Relates to compounds, pharmaceuticals, compositions and combination preparations as defined in.

A further object of the present invention is, for example, an iron metabolism disorder, especially associated with or resulting in elevated iron levels and especially iron overload, diseases associated with or caused by elevated iron levels or iron overload, iron with or leading to elevated iron levels. A method for the prophylaxis and treatment as defined above for the prevention and/or treatment of storage disorders and disorders with ineffective red blood cell production, comprising a compound, medicament, composition or combination as defined above. A method comprising the step of administering the formulation to a patient (human or animal) in need thereof.

There, the disease associated with, associated with, caused by or resulting in elevated iron levels or iron overload, is as defined above.

A further object of the invention relates to the use of a compound as defined above, in particular for the prevention and treatment and for the preparation of a medicament of any of the signs, conditions, disorders or diseases defined above.

The compounds according to the invention of the general structural formulas (A-I) and (I) can basically be obtained by the methods described below, as shown in the general procedure (general scheme). Therefore, a further object of the present invention is a method of producing a compound of general formula (AI) as described herein,
a) compound of formula (a)

With a compound of formula (b) NH—R ¹ R ²
Compound of formula (c)

Obtaining (c),
b) the compound (c) is replaced by a compound of the formula (d)

(D) (n=0-7, preferably 0-5, preferably 0-1 or 2)
Further reaction with a compound of formula (AI) to obtain a compound of formula (AI)
R ¹ , R ² , Z, A ¹ , R ³ and Ar are processes with the meaning defined above. In principle, the order of the reaction steps is arbitrary. It is further possible to react compound (a) with compound (d) and subsequently with compound (b) to give a compound of formula (AI). As further detailed in the examples below, some further intermediate steps are possible and some intermediate compounds are obtained. Some of the intermediate compounds are also new compounds and will be covered by the present invention.

A further object of the invention is a method of producing a compound of general formula (I) as described herein,
a) compound of formula (a)

(A)
With a compound of formula (b) NH—R ¹ R ²
Compound of formula (c)

Obtaining (c),
b) the compound (c) is replaced by a compound of the formula (d)

(D) (n=0-7, preferably 0-5, preferably 0-1 or 2)
Further reacting with a compound of formula (I) to obtain a compound of formula (I),
X ¹ , Y ¹ , R ¹ , R ² , Z, A ¹ , R ³ and Ar are processes with the meanings defined herein. In principle, the order of the reaction steps is arbitrary. It is further possible to react compound (a) with compound (d) and subsequently with compound (b) to give a compound of formula (I). As further detailed in the examples below, some further intermediate steps are possible and some intermediate compounds are obtained. Some of the intermediate compounds are also new compounds and will be covered by the present invention.

General scheme 1

In the formula, Rx represents an arbitrary substituent to X ^4, and n corresponding to Y ¹ represents an integer defined in relation to A ¹ in the general scheme I-1.

Wherein Ar has the meaning as defined herein and may correspond to Het-2.

General scheme 4

General scheme 6

General scheme 7

General scheme 8

Wherein Rx represents an optional substituent R ⁴ to Ar=Het-2 as defined herein General Scheme 9

Ry=Ar has the meaning as defined herein and may correspond to Het-2.

General scheme 11

General scheme 12

Wherein Y ¹ represents an optional substituent to X ⁴ as defined herein Rx represents an optional substituent to phenyl as defined herein Ry=Ar is herein General Scheme 13 with defined meaning and may correspond to Het-2

Ry=Ar has the meaning defined herein and may correspond to Het-2 in the general scheme 14

In the formula, Rx represents an arbitrary substituent for X ¹ or X ^4, and is a general scheme corresponding to Y ^1.

Ry=Ar has the meaning as defined herein and may correspond to Het-2 in the general scheme 16

Ry=Ar has the meaning as defined herein and may correspond to Het-2 in the general scheme 18

General scheme 19

Ry=Ar has the meaning defined herein and may correspond to Het-2 in the general scheme 20

General scheme 21

Ry=Ar has the meaning defined herein and may correspond to Het-2.

General scheme 23

General scheme 24

Ar has the meaning defined herein and may correspond to Het-2 in the general scheme 25

Ry=Ar has the meaning defined herein and may correspond to Het-2 in the general scheme 26

General scheme 27

Ar has the meaning defined herein and may correspond to Het-2 Rx = any substituent of phenyl as defined herein General Scheme 28

General scheme 41

General scheme 42

Intermediate scheme A

Scheme B

Scheme C

General scheme KI

General scheme K-II

Ry = phenyl substituent as defined herein [Examples]
The invention will be explained in more detail by the following examples. These examples are illustrative only, and one of ordinary skill in the art can extend specific examples to the claimed compounds.

Pharmacological assay 1. Hepcidin internalization assay (J774)
This cellular assay allows quantification of hepcidin-ferroportin (Fpn) binding through microscopic detection of internalization of fluorescently labeled hepcidin into J774 cells. J774 is a mouse macrophage cell line that has been shown to express Fpn endogenously upon incubation with iron (Knutson et al, 2005). The binding of hepcidin to Fpn triggers internalization and degradation of both hepcidin and Fpn. However, the hepcidin-bound TMR (6-carboxytetramethylrhodamine) fluorophore remains associated with cells after degradation of the hepcidin peptide backbone. Therefore, microscopic detection of cell-associated TMR fluorescence is a measure of hepcidin binding to Fpn and internalization of hepcidin and Fpn. When TMR-hepcidin is blocked from binding to Fpn, cellular TMR fluorescence remains low (Durrenberger et al., 2013). The effect of low molecular weight Fpn inhibitor compounds in this assay was evaluated in vitro as described below.

J774 cells harvested from approximately 80% confluent culture were treated with complete medium (DMEM, 10% FBS, 1% penicillin-streptomycin) containing 200 μM Fe(III)NTA (nitrilotriacetic acid), 100 μl/well of 96-well MicroClear plate ( Greiner; Catalog 655090) was seeded at 8×10 ⁵ cells/ml and grown at 37° C., 5% CO ₂ . After overnight incubation, cells were washed 3 times with pre-warmed DMEM without phenol red, after final wash 30 μl/well DMEM (without phenol red) was added and 10 μl/well of test compound. Dilution series were added in triplicate. J774 cells were pre-incubated with the test compounds for 15 minutes at 37° C., 5% CO ₂ before adding TMR-hepcidin at a final concentration of 25 nM. Cells were incubated for 2 hours at 37° C., 5% CO ₂ in a total volume of 50 μl, then Hoechst 33342 dye was added to a final concentration of 0.5 μg/ml to stain the nuclei, and 37° C., 5%. Incubated with CO ₂ for an additional 10 minutes. Cells were washed 3 times with PBS and fixed in 100 μl of 4% paraformaldehyde in PBS for 15 minutes at room temperature. After removing the paraformaldehyde solution, the cells were washed 3 times with PBS, leaving 100 μl/well and the plates were sealed with foil plate seals. TMR (530-550 nm excitation/575-625 nm emission/400 ms exposure time) and Hoechst 33342 (360-370 nm excitation/420-460 nm emission/10 ms exposure time) fluorescence images, ScanR plate imager with 20× high NA objective ( Olympus). Four images were acquired per well and the fluorescence channel covered approximately 1500 cells per well. The acquired image data was analyzed by ScanR image analysis software. Image analysis included detection of nuclei (Hoechst 33342 fluorescence), identification of cell-associated regions, application of virtual channels, and thresholding for rolling ball background reduction, followed by a quantitative measure of internalized TMR-hepcidin. The application of the Sum (Mean) algorithm for measuring TMR fluorescence associated with cells as was included. Prism 5 software (GraphPad Software Inc., Version 5.02) "log (inhibitor) corresponding answer" of using curve fitting, _{IC 50} values were calculated using a Sum (Mean) raw data. For each data set, the fit of the "log (inhibitor) vs. response (3 parameters)" model was compared to the fit of the "log (inhibitor) vs. response-variable slope (4 parameters)" model and the IC of the preferred model was compared. ₅₀ data were used. The IC ₅₀ data for Fpn inhibitors tested in the hepcidin internalization assay are listed in Table 1. The IC ₅₀ of unlabeled hepcidin in this assay is 0.015±0.011 μM.

Table 1 Mean (AVE) IC ₅₀ data for Fpn inhibitors tested in the hepcidin internalization assay are shown for multiple measurements.

2. Biophysical Ferroportin-hepcidin Binding Assay This biophysical assay was developed to more directly confirm the inhibition of hepcidin binding to ferroportin (Fpn). Incubation of TMR-hepcidin with purified human Fpn isolated from Pichia pastoris yeast cells expressing human Fpn with a C-terminal FLAG affinity tag (Boncorcorsi di Patti, 2014) resulted in fluorescence of the TMR-hepcidin ligand. This results in an increase in polarization (FP). Low molecular weight Fpn inhibitors were tested for inhibition of TMR-hepcidin binding to Fpn, as detected by a dose-dependent reduction of TMR FP signal, as described in detail below.

A mixture of 1.3 μM human Fpn and 30 nM TMR-hepcidin in FP assay buffer containing 50 mM Tris-HCl pH 7.3, 200 mM NaCl, 0.02% DDM, 0.1% BSA, 384 well black low volume. Round bottom plates (Corning, Catalog 3677) were plated at 16 μl/well. 8 μl of serial dilutions of test compound were added in duplicate to reach final Fpn and TMR-hepcidin concentrations of 1 μM and 20 nM, respectively. Plates were incubated at room temperature for 90 minutes and parallel (S) and vertical (P) fluorescence was measured on a Synergy H1 fluorescence reader (BioTek). The FP value was calculated in mP according to the following formula.

IC ₅₀ values were determined using mP values calculated as described for the hepcidin internalization assay and are listed in Table 2. The IC ₅₀ of unlabeled hepcidin in this assay is 0.37±0.067 μM.

Table 2 Mean (AVE) IC ₅₀ data for Fpn inhibitors tested in the biophysical hepcidin-ferroportin binding assay are shown for multiple measurements.

3. Inhibition of Ferroportin-Mediated Iron Delivery Activity in an Iron Response Assay In this assay, a β-lactamase (BLA) reporter gene fused to the human ferritin promoter and associated iron regulatory elements (IRE) contained within the 5′ untranslated region of ferritin mRNA. Intracellular iron levels are indirectly measured by monitoring the activity of. Expression of ferroportin (Fpn) in such cell lines results in iron efflux and lower iron levels, as reflected by the low activity of the reporter gene. On the other hand, inhibition of Fpn-mediated iron efflux results in elevated cellular iron levels detected as increased reporter gene activity. The low molecular weight Fpn inhibitor compounds were tested for dose dependent effects in this in vitro iron response assay as described below.

HEK-293 cell line #354 was inserted into (i) a derivative of the doxycycline-inducible pTRE-Tight-BI plasmid (Clontech, Catalog 631068) and a human Fpn-GFP fusion construct and (ii) human ferritin promoter-BLA reporter gene. Was prepared by stable incorporation into a derivative of the HEK-293 Tet-ON Advanced cell line (Clontech). To make the ferritin-BLA reporter gene construct, a 1.4 kb fragment of the human ferritin H promoter was PCR-ed from human genomic DNA (forward primer 5'-CAGGTTTTGTGAGCATCCTGAA-3'; reverse primer 5'-GGCGCGCGACTAAGGAGAGG-3'). Amplify and pcDNA™6. ² /cGeneBLAzer™-insert before the BLA gene present in the DEST plasmid (Invitrogen, catalog 12578-043), thereby replacing the original CMV promoter and ferritin gene approximately 170 bp upstream of the start codon of the reporter gene. IREs that regulate the translation of #354 cells were harvested from approximately 80% confluent culture medium, 10% FBS (Clontech, catalog 631106), 1% penicillin-streptomycin, 200 μg/ml hygromycin B (Invitrogen, catalog 10687-010), blasticidin 5 μg/ ml (Invitrogen, Catalog R210-01), DMEM/F12 GlutaMAX™ medium (Invitrogen, Catalog 31331-028) containing 4 μg/ml doxycycline (Clontech, Catalog 631311), 50 μl/well in 384-well PDL coated plates. 1.8×10 ⁵ cells/ml were seeded and grown at 37° C., 5% CO ₂ . After overnight incubation, 10 μl/well dilution series of test compound was added in quadruplicate and plates were further incubated overnight at 37° C., 5% CO ₂ . Cells were washed 3 times with HBSS and remained at 25μ per well. BLA activity was detected by adding 5 μl/well GeneBlazer reagent CCF4-AM (Invitrogen, Catalog K1085) to the cells. After incubating the plates for 60 minutes at 18° C. in the dark, blue and green fluorescence signals were measured on a Safire2 fluorescence plate reader (Tecan) with excitation at 410 nm and emission at 458 nm (blue) and 522 nm (green). The ratio of blue/green fluorescence as a measure of BLA activity was calculated and EC ₅₀ values were determined with the calculated blue/green fluorescence ratio as described for the hepcidin internalization assay. EC ₅₀ data for the Fpn inhibitors tested are shown in Table 3. The EC ₅₀ for hepcidin in this assay is 0.096±0.063 μM (n=37).

Table 3 Mean (AVE) EC ₅₀ data for Fpn inhibitors tested in the iron response assay are shown for multiple measurements.

4. Ferroportin Internalization and Degradation Assay Using HEK-293 cell line #354 (described in Example 3), the compound induces ferroportin (Fpn) internalization and degradation by fluorescence activated cell sorting (FACS). Ability was measured. HEK-293#354 cells grown in doxycycline-containing medium induced expression of human Fpn-GFP fusion protein on the cell surface. Data from 10 independent experiments indicate that incubation of HEK#354 cells in the presence of 4 μg/ml doxycycline for 48 hours induces an average of 42.6%±6.4% Fpn-GFP positive cells. Indicated. Low molecular weight Fpn inhibitor compounds were tested for dose-dependent effect on Fpn-GFP mean fluorescence intensity (MFI) on HEK-293 cell line #354 as described below.

HEK#354 cells were harvested from approximately 80% confluent culture medium, 10% FBS (Clontech, Catalog 631106), 1% Penicillin-Streptomycin (Invitrogen, Catalog 15140-122), 200 μg/ml Hygromycin B (Invitrogen, Catalog 10687). -010), blasticidin 5 μg/ml (Invitrogen, catalog R210-01), 4 μg/ml doxycycline (Clontech, catalog 631311) in DMEM/F12 GlutaMAX™ medium (Invitrogen, catalog 31331-028), 50 μl. /Well 384-well plate (Greiner; catalog 781091) was seeded at 0.6 x 10 ⁶ cells/ml and grown at 37°C, 5% CO ₂ . After overnight incubation, 10 μl/well dilution series of test compound was added in quadruplicate and plates were further incubated overnight at 37° C., 5% CO ₂ . The cells were washed once with FACS buffer (PBS containing 1% FBS, 2 mM EDTA and 0.05% NaN ₃ ) and added to FACS buffer containing 0.5 μg/ml propidium iodide (Sigma, Catalog P4864). Harvested and analyzed by flow cytometer (CANTO™ II, BD Biosciences). Viable HEK#354 cells were gated as a propidium iodide negative population and analyzed for Fpn-GFP expression. Calculate the MFI of Fpn-GFP of over 2000 viable cells for each compound dilution using FlowJo (Tree Star's, Oregon) to determine the ability of the Fpn inhibitor to induce internalization and degradation of Fpn-GFP. Calculated as described for the hepcidin internalization assay. EC ₅₀ data for Fpn inhibitors tested in the ferroportin internalization and degradation assay by FACS are listed in Table 4. The mean EC ₅₀ value for hepcidin in this assay is 0.004±0.002 μM.

Table 4 Mean (AVE) EC ₅₀ data for Fpn inhibitors tested in the ferroportin internalization and degradation assay are shown for multiple measurements.

5. Ferroportin Ubiquitination and Degradation Exposure of cells expressing ferroportin (Fpn) to hepcidin is known to induce ubiquitination and subsequent Fpn internalization and degradation (Qiao, 2012). The ability of Fpn inhibitors to induce ubiquitination and degradation of Fpn was examined in an immunoprecipitation assay using the J774 mouse macrophage cell line that expresses Fpn when treated with iron.

J774 cells (DSMZ, catalog ACC170) were grown in medium (DMEM Gibco catalog 11971-025, 10% heat inactivated FBS Gibco catalog 10500-064) containing 200 μM Fe(III)-NTA in 10 cm tissue culture dishes (Greiner catalog 664160). 15 ml of 1% penicillin-streptomycin Gibco catalog 15140-122) was seeded at 0.8×10 6 cells/ml and grown overnight at 37° C., 5% CO ₂ . Cells were incubated with synthetic human hepcidin (Bachem, Catalog H-5926) or Fpn inhibitor compounds for 10 or 120 minutes. Cells were washed, lysed with ice-cold lysis buffer (Pierce, Life Technologies, catalog 87787) containing 1X HALT protease inhibitor cocktail (Life technologies, catalog 78429) and 10 mM iodoacetamide (Sigma, catalog I6125), and ubiquitin. The stabilized protein was stabilized. Immunoprecipitations were performed using the Pierce Classic IP Kit (Life Technologies, Catalog 26146) according to the manufacturer's protocol. Briefly, 2 mg of protein in 1.25 ml of IP lysis buffer was mixed with control agarose beads for 1 hour at 4° C. and incubated to preclear the lysate and reduce non-specific signal. Unbound lysates were then incubated overnight with 12 μg/reaction of affinity-purified anti-Fpn antibody F308 raised against the mouse Fpn amino acid 224-308 GST fusion protein. Immune complexes were captured by pipetting 14 μl of precipitated Pierce Protein A/G Plus Agarose beads (Life Technologies, Catalog 20423) per reaction for 1.5 h at 4° C. with gentle inversion mixing. Incubated. The beads were washed and the immune complexes were directly eluted with 75 μl of SDS NuPAGE LDS sample buffer (Life Technologies, catalog NP0007) containing DTT (Life Technologies, catalog NP0009).

After immunoprecipitation, rabbit anti-mouse MTP1 antiserum (Alpha Diagnostic International, catalog MTP11-A) and mouse anti-mono- and polyubiquitinated conjugated monoclonal antibodies (Enzo Lifesciences, catalog BML-) for detecting ferroportin and ubiquitin, respectively. Samples were analyzed by Western blotting with PW8810). Mouse monoclonal anti-rabbit IgG light chain (Abcam, catalog ab99697) and anti-mouse IgG H&L (Abcam, catalog ab6789) HRP conjugate were used as secondary antibodies.

A selection of 11 Fpn inhibitors was tested in this assay and compared to hepcidin. As shown in FIG. 1 and Table 5, when cells were treated with an Fpn inhibitor, rapid ubiquitination occurred within 10 minutes (FIG. 1, upper panel), and Fpn degradation occurred after 2 hours (FIG. 1, lower panel). ). The extent of Fpn degradation by Fpn inhibitors was comparable to the effect of hepcidin. However, hepcidin treatment resulted in ubiquitinated Fpn with higher molecular weight compared to Fpn inhibitor treatment, suggesting polyubiquitination by hepcidin versus monoubiquitination by Fpn inhibitor, respectively.

Table 5 Summary of Fpn inhibitors tested in the Fpn ubiquitination and degradation assay. The effect of treatment with Fpn inhibitors on Fpn degradation and Fpn ubiquitination was scored by visual inspection of Western blots (+compared to hepcidin;-no effect; +/-intermediate effect).

Figure 1 Fpn inhibitors trigger ubiquitination and degradation of Fpn expressed in mouse macrophage cell lines. J774 cells were incubated with Fe(III)-NTA overnight to induce Fpn expression. The cells were then treated with about 10 times the IC ₅₀ concentration of hepcidin (hepcidin, 150 nM) or Fpn inhibitor Example Compound #208 (210 nM), Example Compound #167 as determined by the hepcidin internalization assay (see Table 1). (1.5 μM), Example compound No. 127 (120 nM), and Example compound No. 152 (40 nM) for 10 minutes or 120 minutes, then harvested and immunoprecipitated with anti-Fpn antibody F308. Mock treated cells were harvested after 120 minutes (control).

Immunoblotting of the immunoprecipitates with the anti-Fpn antibody MTP1 revealed the disappearance of ferroportin after 120 minutes of treatment with the Fpn inhibitor to a similar extent as the sample treated with hepcidin (top panel). Rapid ubiquitination of Fpn was observed 10 minutes after treatment of cells with Fpn inhibitor and hepcidin. The protein molecular weight standard is shown in kD on the left.

6. Inhibition of iron efflux by ferroportin inhibitors The activity of hepcidin and ferroportin inhibitor compounds on their ability to block iron delivery through ferroportin was tested in T47D cells (ECACC, catalog 85102201) as described below.

Cells were plated in 24-well plates (Greiner, Catalog 662160) containing 350,000 cells/well and 100 μM ⁵⁸ Fe ( ⁵⁸ Fe(II) sulfate in 500 μM L-ascorbic acid (Sigma Aldrich, Catalog No. 795437) containing growth medium. , Vifor Pharma Batch ROR No. 3085). Cells were loaded with 500 μl of iron uptake buffer (IUB; PIPES 40 mM, catalog P1851, glucose monohydrate 10 mM, catalog 49158, sodium chloride 260 mM, catalog 71379, potassium chloride 20 mM, catalog P9541, magnesium sulfate 2 mM, catalog 63138, Sigma Aldrich. ), and then twice with depletion buffer (2 min incubation, 100 μM BPDS, catalog 11890 and 500 μM Na ₂ S ₂ O ₄ , catalog 157953, Sigma Aldrich, IUB) and twice with IUB again. Serial dilutions of hepcidin (Bachem) or ferroportin inhibitors (4 μM to 0.0064 μM, 5-fold dilutions) were added in a total volume of 0.6 ml per well. Cells were incubated for 20 hours at 37°C, 5% CO2. The supernatant was collected and ⁵⁸ Fe was measured using inductively coupled plasma mass spectrometry (ICP-MS, Thermo Scientific, Element 2). Pellets were harvested for protein concentration determination. Results are plotted as ⁵⁸ Fe ng in supernatant per mg protein in cell lysate. Example compound #127 inhibited iron efflux with similar potency as the endogenous Fpn ligand hepcidin (Figure 2).

FIG. 2 Representative iron efflux inhibition of hepcidin (IC ₅₀ : 0.086 μM) and Example compound #127 (IC ₅₀ : 0.080 μM).

7. Hypoferraemia in naive mice Injection of synthetic hepcidin into wild-type (WT) naive mice resulted in maximal effect on reduction of serum iron levels (40-50% from vehicle control) 3-4 hours after treatment (Rivera). , 2005; FIG. 3A). This data suggested that injected hepcidin triggers internalization of ferroportin (Fpn) on duodenal enterocytes and splenocytes, causing a rapid drop in serum iron. Similarly, orally administered low molecular weight Fpn inhibitors reduced serum iron levels in WT C57BL/6 mice in a dose-dependent manner with potency comparable to hepcidin (FIG. 3B). This data confirmed the use of WT mice as a simple and reliable model to test the acute effects of Fpn inhibitors in vivo.

Nine-week-old female C57BL/6 mice (Janvier, France) were fed a standard diet (Harlan Provimi Kliba 3436) and orally (po) treated with a compound in a volume of 10 ml/kg body weight or the corresponding amount of vehicle. .. Fpn inhibitors were formulated in 0.5% methylcellulose/water or 20% cremophor EL®/water and orally administered to mice at 10, 30 or 100 mg/kg body weight. After 3 hours, the mice were anesthetized in an isoflurane chamber before death and blood was collected by retro-orbital bleeding. Mice were sacrificed by cervical dislocation and spleen, liver and duodenum were harvested and used for biomarker analysis. All experiments were performed according to a license approved by the responsible veterinary authority. Serum was isolated by centrifuging the blood into gel-containing microtainer® and serum iron was measured by the MULTIGENT Iron assay (Abbott Diagnostics, 6K95). One-way ANOVA with Bonferroni's multiple comparison test was performed using 8 mice per group to analyze statistical differences between experimental groups. The efficacy of selected Fpn inhibitors in WT C57BL/6 mice is shown in Table 6.

FIG. 3 Serum iron reduction induced by a ferroportin inhibitor by hepcidin and Example Compound 94 (Example Compound 94).

A Kinetics of serum iron in naive C57BL/6 mice injected intraperitoneally (ip) with synthetic hepcidin (5 mg/kg) for the times indicated. *-***- indicates a statistically significant decrease in serum iron compared to PBS treated mice.

B Serum iron levels in naive C57BL/6 mice treated with either the indicated amount of hepcidin (ip) or Example Compound 94 (Example Compound #94) (po) for 3 hours.

Table 6 Efficacy of Fpn inhibitors tested in the naive mouse hypoferraemia model.

Serum iron reduction was induced by selected ferroportin inhibitors orally administered to naive WT C57BL/6 mice at 10, 30 and 100 mg/kg. Relative serum iron reduction at 3 hours post-dose was calculated by subtracting the mean serum iron level of animals treated with the Fpn inhibitor from that of vehicle treated animals. The difference in mean serum iron values between the vehicle and compound treated groups was then divided by the mean value of serum iron in the vehicle control group and listed as a percentage.

8. Prevention of Iron Absorption in Anemia Rats To evaluate the in vivo efficacy of ferroportin (Fpn) inhibitors in blocking iron absorption, a series of Fpn inhibitors were tested in an anemia rat model for iron absorption. Wistar rats (3-4 weeks old, n=5, Janvier Labs) were fed a low iron diet (Provimi-Kliba) until the hemoglobin (Hb) level reached 7-8 g/dl one day before administration of the Fpn inhibitor compound. Catalog 2039) was given. Test compounds formulated in methylcellulose or Cremophor were administered orally 1 hour before oral application of 0.5 mg/kg ferrous sulfate. 1 hour before iron administration (-1 hour), immediately after administration of Fpn inhibitor (0 hour) and 1 hour after administration of test compound (1 hour), 3 hours (3 hours) and occasionally 6 hours later (6 hours). ), a blood sample was collected by tail vein puncture. Serum iron levels were measured (Abbott Diagnostics, Catalog 6K95) and inhibition of serum iron elevation 3 hours after test compound administration was calculated as a measure of the effectiveness of Fpn inhibitors in blocking iron absorption (Table 7). As shown in FIG. 4, oral administration of the Fpn Inhibitor Example Compound No. 55 at 3 mg/kg, 10 mg/kg or 30 mg/kg, compared to serum iron levels in vehicle-treated animals prior to iron administration, When corrected for baseline serum iron levels in vehicle-treated animals that did not receive ∑∑, serum iron levels were reduced by 54%, 72%, and 89%, respectively, 3 hours after iron administration.

Table 7 Fpn inhibitors were tested in an anemia rat model for inhibition of iron absorption. The relative inhibition values (%) of the serum iron level corrected to the mean baseline serum iron level of the control group which did not receive the oral iron administration, as compared with the control group which was treated with the vehicle before the iron administration are shown. The mean values of the groups treated with the indicated doses of Fpn inhibitors (n=5) are shown. Shows the statistically significant (two-way ANOVA by Bonferroni post hoc) difference observed between the compound-treated and vehicle-treated groups (***p<0.001; **p<0. 01, *p<0.05).

Figure 4 Dose-dependent block of iron absorption in anemia rats by Fpn inhibitor Example Compound #55. One hour before oral administration of ferrous sulfate (0.5 mg/kg), Example Compound No. 55 was administered at 3 mg/kg (light blue line), 10 mg/kg (green line) or 30 mg/kg (dark blue line). ) Orally. Administration of Example Compound No. 55 was statistically significant (p<0.001) and dose-dependent inhibition of the increase in serum iron observed 3 hours after iron administration in animals treated with vehicle (red line). Brought in. Also shown is the baseline serum iron level in the vehicle treated group that did not receive a fixed dose of iron (black line). Means are plotted with standard deviation for each treatment group and time point.

9. Correction of hyperironemia in β2-microglobulin-deficient mice Hepcidin (Hamp1), hemochromatosis protein (HFE), hemojuvelin (HJV) and transferrin receptor 2 (TFR2) The mutation causes iron overload in mice and humans. HFE, HJV and TFR2 molecules on hepatocytes are required for proper hepcidin production signaling, and their deficiency results in pathophysiologically low hepcidin levels and excessive iron absorption. HFE mutations are the most frequent cause of hereditary hemochromatosis (HH) in Caucasian adults. HFE is an MHC class I-like membrane molecule that associates with β2-microglobulin and is involved in hepcidin transcriptional regulation through the bone morphogenetic protein receptor (BMPR) pathway. HFE −/− mice have reduced hepcidin levels and develop hyperironemia and elevated liver iron levels, making them a suitable animal model for studying human iron overload (Zhou, 1998). Since β2-microglobulin is required for cell surface expression and function of HFE, β2-microglobulin-deficient mice (b2m−/−) develop hyperironemia and hemochromatosis, similar to HFE−/− animals. (Rothenberg and Voland, 1996). B2m−/− mice were used as a model for iron overload, as HFE−/− mice are not available. Pilot studies have confirmed that HFE-/- and b2m-/- mice have similar iron metabolism-related parameters.

Female and male homozygous b2m−/− mice were supplied from Jackson Laboratories (B6.129P2-B2mtm1Unc/J, stock number: 002087) at 6-7 weeks of age and were fed standard samples (Harlan Provimi Kliba 3436) ad libitum. It was Age and gender matched WT C57BL/6 mice are supplied by Charles River. To test the acute effects of ferroportin (Fpn) inhibitors on iron overload, b2m−/− mice were treated with a volume of compound of 10 ml/kg body weight or the corresponding amount of vehicle. Fpn inhibitor compounds were formulated in 0.5% methylcellulose/water or 20% cremophor EL®/water and orally administered to mice at 50 mg/kg body weight. WT controls received vehicle only. After 3 hours, the mice were anesthetized in an isoflurane chamber before death and blood was collected by retro-orbital bleeding. Mice were sacrificed by cervical dislocation and spleen, liver and duodenum were harvested and used for biomarker analysis. All experiments were performed according to a license approved by the responsible veterinary authority. Serum was isolated by centrifuging blood into gel-containing microtainer® (BD Biosciences) and serum iron was measured by the MULTIGENT Iron assay (Abbott Diagnostics, Catalog 6K95). Statistical differences between experimental groups were analyzed using 4-9 mice per group and applying one-way ANOVA with Bonferroni's multiple comparison test.

To investigate the effect of Fpn inhibitors Example Compound #40 and Example Compound #94 in iron overload conditions, b2m−/− mice or WT controls were administered an Fpn inhibitor or vehicle for 3 hours. Due to its genetic deficiency, vehicle treated b2m−/− mice showed significantly higher serum iron levels compared to WT mice (FIG. 5, group mean of 60 μM in A and 56 μM in B). Treatment of b2m −/− mice with 50 mg/kg of Example Compound #40 or Example Compound #94 for 3 hours corrected elevated serum iron to the levels observed in the WT controls. These data demonstrated the acute efficacy of low molecular weight ferroportin inhibitors in disease-related models. Serum iron corrections were observed in further studies, as summarized in Table 8.

FIG. 5 Elevated serum iron levels in b2m−/− mice by treatment with ferroportin inhibitor Example Compound #40/methylcellulose (A.) and Example Compound #94/cremophor EL® (B.) for 3 hours. Complete correction of.

Table 8 Fpn Inhibitors Tested in a β2-Microglobulin Deficient Mouse Model for Decreased Elevated Serum Iron Levels 1 hour (#) or 3 hours after oral administration of the indicated doses of Fpn inhibitors to β2-microglobulin deficient mice. Blood was collected in (##) and the serum iron concentration was measured. Relative serum iron level reduction (%) is calculated by subtracting the mean serum iron level of animals treated with the Fpn inhibitor from that of vehicle treated animals. The difference in mean serum iron values between the vehicle and compound treated groups was then divided by the mean value of serum iron in the vehicle control group and listed as a percentage. Due to the significant difference in sex dependence, the values are listed separately for female (♀) and male (♂) animals. Shows the statistically significant (two-way ANOVA by Bonferroni post hoc) difference observed between the compound-treated and vehicle-treated groups (***p<0.001;**p<0. 01, *p<0.05).

10. Prevention of iron overload in β2-microglobulin deficient mice As a result of decreased intestinal hepcidin levels and increased iron absorption, β2-microglobulin deficient (b2m-/-) mice on standard diets have liver, heart and pancreas Accumulate excess iron in. Pilot studies have shown that hepatic iron loading in b2m-/- begins at 3-4 weeks of age and liver iron levels reach up to 4 times the liver iron content of 6-week-old wild-type (WT) mice. .. Furthermore, feeding the low iron content (LID) diet to b2m −/− mice at 3 weeks of age immediately after weaning prevented iron loading of the liver by 6 to 7 weeks of age. The effectiveness of Fpn inhibitors in preventing liver iron accumulation in b2m−/− mice was investigated. Three week old b2−/− mice given LID were administered either Fpn inhibitor or vehicle (methylcellulose; 10 ml/kg). Mice had access to drinking water supplemented with 1 mM ⁵⁸ Fe(II) sulfate and 10 mM ascorbic acid. Administration of Fpn inhibitor or vehicle, followed by exposure to water containing iron was repeated for 14 days. Mice are euthanized and liver and spleen iron content is analyzed by ICP-OES (all iron isotopes) and liver tissue is also analyzed for ⁵⁸ Fe concentration (ICP-MS). The data summarized in Table 9 show that oral administration of the Fpn inhibitor for 2 weeks prevented hepatic iron load and increased splenic iron concentration in b2m −/− mice, and inhibited ferroportin in both the intestine and spleen. It indicates that

These data demonstrate the efficacy of low molecular weight ferroportin inhibitors in preventing hepatic iron load in b2−/− mice, which provides proof of concept in disease-related models.

Table 9 Fpn inhibitors were tested in a β2-microglobulin deficient mouse model for inhibition of liver iron overload.

Livers and spleens were harvested after treatment of β2-microglobulin deficient mice with the indicated doses of Fpn inhibitors for 14 days (po; bid). Total liver and spleen tissue iron concentrations were measured using ICP-OES and ⁵⁸ Fe liver concentrations were measured by ICP-MS. Relative tissue iron levels calculated by normalizing the difference between the mean tissue iron values of animals receiving Fpn inhibitor and the mean tissue iron values of vehicle-treated animals by means of vehicle controls. Change (%). Due to the significant difference in sex dependence, the values are listed separately for female (♀) and male (♂) animals. Shows the statistically significant (two-way ANOVA by Bonferroni post hoc) difference observed between the compound-treated and vehicle-treated groups (***p<0.001;**p<0. 01, *p<0.05). nd, undecided; na, not available.

11. Improvement of anemia, ineffective erythropoiesis and iron overload in a mouse model of intermediate β-thalassemia β-thalassemia is a hereditary anemia caused by a mutation in the β-globin gene of hemoglobin that results in abnormal red blood cells with reduced lifespan. is there. The most severe form, severe thalassemia, requires blood transfusions, resulting in secondary iron overload. Patients with intermediate thalassemia have moderate transfusion-independent anemia but develop iron overload due to inefficient erythropoiesis and chronic suppression of hepcidin production.

As shown in the previous example, an oral ferroportin (Fpn) inhibitor similar to hepcidin blocks ferroportin-mediated iron delivery from cells in vitro and transiently reduced serum iron upon administration in wild-type mice. It was Based on these findings and published studies (Schmidt PJ, et al, Blood 2013, Guo S, et al, JCI, 2013 and Casu C. et al, Blood, 2016), iron absorption from aged red blood cells and Fpn inhibitors were investigated for their ability to prevent iron load of intermediate thalassemia by limiting reuse and improve erythropoiesis. The efficacy of Fpn inhibitors was investigated using a mouse model of transfusion-independent β-thalassemia. Mice with a heterozygous deficiency in the β1 and β2 globin genes (called Hbb th3/+ mice) develop transfusion-independent anemia, ineffective erythropoiesis, splenomegaly and secondary iron overload in the spleen, liver and kidney. To do. Heterozygous Hbb th3/+ mice were supplied from Jackson Laboratories (B6; 129P-Hbb-b1tm1Unc Hbb-b2tm1Unc/J, stock number: 002683) at 8-18 weeks of age and were freely fed with low iron samples during the experiment ( Harlan Provimi Kliba 2039, 13.4 ppm Fe). Hbb th3/+ mice were dosed twice daily with either 20 or 60 mg/kg of compound or methylcellulose as vehicle (10 ml/kg, Sigma, catalog 274429). Between both doses, mice utilized drinking water supplemented with 1 mM ⁵⁸ Fe(II) sulfate (Vifor Pharma, batch number ROR 3096) and 10 mM ascorbic acid (Sigma, catalog 795437) for 6 hours. The concentration of ⁵⁸ Fe(II) sulphate supplied in drinking water was adjusted as an alternative to the intake of a standard rodent diet with an iron content of 250 ppm. ⁵⁸ Fe(II) sulfate and water without ascorbic acid were provided for the remaining 18 hours. In individual experiments, administration of the Fpn inhibitor or vehicle, followed by exposure to water containing iron was repeated for 20-46 days.

As shown previously in wild type and b2m−/− mice, Fpn inhibitors administered for 3 hours in Hbb th3/+ mice efficiently reduced serum iron levels in this mouse strain as well (Table 10). ), demonstrated the ability of these small molecules to cause iron restriction.

Hbb th3/+ mice are anemic with hemoglobin levels in the range 70-80 g/L. Oral administration of Fpn inhibitor for 2 weeks in Hbb th3/+ mice significantly increased hemoglobin levels compared to vehicle treated mice (Table 10). The change in hemoglobin level in the compound-administered group compared to the vehicle-treated group reached 19-22 g/L by the end of the study. Additional hematological parameters were measured on terminal blood using an automated hematology analyzer. Treatment of Hbb th3/+ mice with an Fpn inhibitor increased red blood cell count, hematocrit, decreased reticulocyte concentration and red blood cell distribution width (RDW), indicating improved red blood cell production. Moreover, Hbb th3/+ mice receiving Fpn inhibitors have significantly reduced white blood cell counts in blood compared to the vehicle group, which is beneficial for Fpn inhibitors in the correction of pathologically altered parameters in disease models. The effect was further demonstrated. Therefore, the Fpn inhibitor significantly improved anemia and corrected blood composition in a mouse model of intermediate thalassemia.

Inefficient erythropoiesis in Hbb th3/+ mice causes excessive proliferation of erythroid progenitor cells in the spleen, resulting in splenomegaly. Treatment of Hbb th3/+ mice with Fpn inhibitors significantly reduced spleen weight, highlighting the ability of Fpn inhibitors to reverse splenomegaly (Table 10).

The effect of Fpn inhibitors on erythropoiesis was analyzed by analyzing the percentage of differentiated erythroid progenitor cells in bone marrow and spleen using flow cytometry and the Ter119 (eBioscience, Catalog 17-5921) and CD44 (BioLegend, Catalog 103028) markers. Tested. Bone marrow or spleen cells isolated from Hbb th3/+ mice treated with Fpn inhibitors had a significantly reduced proportion of early erythroid progenitor preerythroblasts, favorable erythroblasts, compared to vehicle-treated Hbb th3/+ mice. It contained basophils and polychromatic erythroblasts and an increased proportion of mature red blood cells (Table 10). These data demonstrated that Fpn inhibitors improved inefficient erythropoiesis in Hbb th3/+ mice, consistent with improved hematological parameters in blood.

Serum erythropoietin levels in Hbb th3/+ mice and thalassemia patients are upregulated due to feedback responses to anemia, hypoxia and inefficient erythropoiesis (Guo et al. JCI, 2013). Hbb th3/+ mice treated with Fpn inhibitors had significantly less serum erythropoietin (DuoSet ELISA R&D Systems, Cat) as compared to the vehicle group, probably as a result of partially corrected anemia and improved erythropoiesis. DY959) was produced (Table 10).

Elevated erythropoietin levels in Hbb th3/+ mice induced overexpression of erythroferon, a red blood cell regulating hormone known to suppress hepcidin (Kautz L. et al, Nat. Genet., 2014). Consistent with the decrease in serum erythropoietin, erythroferon mRNA expression was significantly reduced in the spleens of Fpn inhibitor treated Hbb th3/+ mice compared to those administered vehicle alone (Table 10). Erythroferon is produced by erythroid progenitor cells that proliferate extensively in the spleen of Hbb th3/+ mice as a result of extramedullary erythropoiesis. Therefore, the effect of Fpn inhibitors on erythroferon expression in the spleen is mediated by improved erythropoiesis.

Increased iron demand due to inefficient erythropoiesis and chronically low hepcidin levels in thalassemia patients causes organ iron load and associated pathological conditions such as hepatocellular carcinoma and heart failure (Rivella S. Haematologica, 2015). Hbb th3/+ mice absorb excess iron as a result of high iron content in liver, spleen and kidneys and insufficiently low hepcidin levels for increased ferroportin expression in the duodenum (Gardenghi S., Blood, 2007. ). Total liver iron and ⁵⁸ Fe content in organs of Hbb th3/+ mice treated with vehicle or Fpn inhibitor were analyzed by inductively coupled plasma-optical emission spectrometry (ICP-OES) and inductively coupled plasma mass spectrometry (ICP-MS), respectively. .. ⁵⁸ Fe levels in liver and spleen of Hbb th3/+ mice treated with Fpn inhibitors were significantly lower than those of vehicle-treated mice, indicating that Fpn inhibitors prevent organ iron accumulation. (Table 10).

Since Fpn inhibitors are systemically available, they can block iron delivery in all ferroportin expressing tissues including duodenum, spleen and liver. Therefore, Fpn inhibitors would be expected to prevent iron absorption from the duodenum, but would not be able to remove pre-existing iron in the liver and spleen. In fact, total liver iron in mice treated with Fpn inhibitor or vehicle remained unchanged (not shown). Importantly, Fpn inhibitors significantly reduced ⁵⁸ Fe levels in the spleen and liver of Hbb th3/+ mice, demonstrating the ability of these small molecules to prevent iron loading.

Furthermore, the fluorescent _{indicator, CM-H 2 DCFDA (Thermo} Fisher Scientific, Cat C6827) was used to detect the reactive oxygen species (ROS) in bone marrow cells. Flow cytometric analysis showed that the Fpn inhibitor significantly reduced ROS in mature red blood cells compared to vehicle treated Hbb th3/+ mice (Table 10).

These data demonstrate that an orally administered low molecular weight ferroportin inhibitor in improving anemia and ineffective erythropoiesis, and in reducing splenomegaly and preventing further liver and spleen iron loading in a disease model of intermediate β-thalassemia. Demonstrated disease modifying ability.

Table 10 Efficacy of ferroportin inhibitors in a mouse model of intermediate thalassemia (Hbb th3/+ mice) The indicated Fpn inhibitors were treated for 20 days (Example compounds 1 and 2), 27 days (Example compound 127) or 46. For a day (Example Compound 40), the compound was administered twice a day. Data are expressed as the difference from the vehicle control group for hemoglobin and as% change relative to the vehicle control group for all other parameters shown.

Preparation of Example Compounds General Experimental Details Commercially available reagents and solvents (HPLC grade) were used without further purification. 1 H NMR spectra were recorded on a Bruker DRX 500 MHz spectrometer, a Bruker DPX 250 MHz spectrometer or a Bruker Avance spectrometer 400 MHz in deuterated solvent. Chemical shifts (δ) are in parts per million.

The compound was purified by flash column chromatography on normal phase silica on a Biotage Isolera system using the appropriate SNAP cartridge and gradient. Alternatively, compounds were purified in reverse phase using the Biotage Isolera system with a suitable C18 SNAP cartridge and reverse phase eluent or preparative HPLC (where otherwise noted).

Analytical HPLC-MS

Abbreviations AcOH Acetic acid AIBN 2,2'-azobis(2-methylpropionitrile)
BH ₃ Borane Boc ₂ O Di-tert-butyldicarbonate CaCO ₃ Calcium carbonate CBz Benzyloxycarbamate CDI 1,1′-Carbonyldiimidazole CHCl ₃ Chloroform d (one or more) days DAST N-ethyl-N-(tri) Fluoro-λ-4-sulfanyl)ethanamine DBU 1,8-diazabicycloundec-7-ene DCC N,N′-dicyclohexylcarbodiimide DCE 1,2-dichloroethane DCM dichloromethane DIAD diisopropylazodicarboxylate DIPEA N,N- Diisopropylethylamine DMAP N,N-dimethylpyridin-4-amine DMF N,N-dimethylformamide Et ₂ O diethyl ether EtOAc ethyl acetate EtOH ethanol h (one or more) hours HATU 1-[bis(dimethylamino)methylene]- 1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate HCl hydrochloric acid HPLC high performance liquid chromatography IPA isopropyl alcohol K ₂ CO ₃ potassium carbonate KO ^t Bu potassium tert-butoxide KHMDS potassium 1 , 1,1,3,3,3-hexamethyldisilazane-2-ide KHSO ₄ potassium bisulfate LiAlH ₄ lithium aluminum hydride LiCl lithium chloride LiOH lithium hydroxide MeCN acetonitrile MeI methyl iodide MeOH methanol min (1 or more) ) Min MW molecular weight NaBH ₄ sodium borohydride NaHCO ₃ sodium bicarbonate NaH sodium hydride (60% in mineral oil)
NaOH sodium hydroxide NBS N-bromosuccinimide NCS N-chlorosuccinimide NH ₄ Cl ammonium chloride Pd / C palladium on carbon PdCl ₂ (dppf) dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II)
Pd ₂ dba ₃ tris(dibenzylideneacetone)dipalladium (0)
PPh ₃ triphenylphosphine PTSA p-toluenesulfonic acid TBME tert-butyl methyl ether TBSCl tert-butyldimethylsilyl chloride TEA triethylamine TFA trifluoroacetic acid TMOF orthoformate trimethyl xanthophos 4,5-bis(diphenylphosphino)-9,9- Dimethylxanthene intermediate Scheme A above:
tert-Butyl N-[(3-fluoropyridin-2-yl)methyl]carbamate (A1)

3-Fluoropyridine-2-carbonitrile (8.0 g, 6.55 mmol), di-tert-butyl dicarbonate (15.7 g, 72.07 mmol), TEA (10.05 ml, 72.07 mmol) in EtOH (300 ml). ) Was purged with N ₂ . Pd/C (10 wt%, 0.7 g, 6.55 mmol) was added and the reaction mixture was stirred under hydrogen atmosphere for 16 hours. The reaction mixture was filtered through celite, rinsed with MeOH (100 ml) and the filtrate removed under vacuum to give the crude product. Purification by flash column chromatography (gradient elution 0-70% EtOAc/heptane) gave the title compound (11.3 g, 72%) as an off-white solid.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.41-8.31 (m, 1H), 7.65 (ddd, J=10.1, 8.3, 1.3 Hz, 1H) ), 7.38 (dt, J=8.5, 4.4 Hz, 1H), 7.18 (s, 1H), 4.30 (d, J=5.4 Hz, 2H), 1.37 (s). , 9H)
HPLC MS (Method A): [m/z]: 226.9 [M+H] ^+.
(3-fluoropyridin-2-yl)methanamine dihydrochloride (A2)

In a manner similar to General Procedure 2 for 2 hours at 40° C. in tert-butyl N-[(3-fluoropyridin-2-yl)methyl]carbamate (A1) (11.3 g, 47. 45 mmol) and 12M HCl (59.3 ml, 711.72 mmol) gave the title compound (9.7 g, 100%) as an off-white solid.

1H-NMR (methanol-d4, 500 MHz): d[ppm]=8.48 (dt, J=4.7, 1.3 Hz, 1H), 7.69 (ddd, J=9.7, 8.5). , 1.2 Hz, 1H), 7.50 (dt, J=8.8, 4.5 Hz, 1H), 4.37 (s, 2H)
HPLCMS (Method A): [m/z]: 126.9 [M+H] ^+.
Scheme B above:
(4,6-Dimethylpyridin-3-yl)methanamine hydrochloride (B1)

4,6-Dimethylpyridine-3-carbonitrile (0.15 g, 1.135 mmol) in MeOH (150 ml) at room temperature using H ₂ at 50 bar at room temperature at 1 ml/min in 1M HCl (1 ml). Subjected to H-Cube with 10% palladium on carbon at flow rate. The solvent was evaporated in vacuo to give the title compound (190mg, 64%) as a white solid. Used without purification.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.74-8.66 (m, 1H), 8.62-8.42 (m, 3H), 7.76-7.64( m, 1H), 4.23-4.13 (m, 2H), 2.66-2.63 (m, 3H), 2.58-2.54 (m, 3H).
HPLC MS (Method E): [m/z]: 136.9 [M+H] ^+.
Scheme C above:
2-(Hydroxymethyl)benzonitrile (C1)

1M BH ₃ in THF (1.51 ml) was added to an ice-cooled (0° C.) solution of 3-formylpyridine-2-carbonitrile (200 mg, 1.51 mmol) in THF (5 ml). The reaction was warmed to room temperature and stirred for 15 hours. The reaction was poured into ice/water (25 ml). The aqueous layer was extracted with EtOAc (3 x 20 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and the solvent was evaporated to give a brown oil. Purification by flash column chromatography (gradient eluting with 20-100% EtOAc/heptane) provided the title compound (45.5 mg, 22.4%) as a yellow solid.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.55 (dd, J=4.7, 1.4 Hz, 1H), 8.01-7.95 (m, 1H), 7.49. (Dd, J=8.0, 4.7 Hz, 1H), 4.89 (s, 2H)
HPLCMS (Method A): [m/z]: 134.85 [M+H] ^+.
2-{[(tert-butyldimethylsilyl)oxy]methyl}benzonitrile (C2)

1M TBSCl/(0.369 ml, 0.369 mmol) in DCM was added to 3-(hydroxymethyl)pyridine-2-carbonitrile (C1) (45 mg, 0.335 mmol) and imidazole (46 mg, 0.671 mmol) in DMF( 2 ml) in solution. The reaction was stirred at room temperature for 15 hours. The solvent was evaporated and the crude product was purified by flash column chromatography (eluting with a gradient of 0-50% EtOAc-Heptane) to give the title compound (44 mg, 52.8%) as a yellow oil.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.60-8.58 (m, 1H), 8.10-7.96 (m, 1H), 7.53 (dd, J=8). 0.0, 4.7 Hz, 1H), 4.94 (s, 2H), 0.95 (s, 9H), 0.15 (s, 6H)
HPLC MS (Method A): [m/z]: 249.00 [M+H] ^+.
(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)methanamine (C3)

2M LiAlH ₄ in THF (0.09 ml) was cooled with 3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridine-2-carbonitrile (C2) (44 mg, 0.18 mmol) in THF (3 ml) with ice. The solution (0° C.) was added dropwise. The reaction was warmed to room temperature and stirred for 2 hours. Diethyl ether (5 ml) was added followed by H ₂ O (1 ml), then 20% w/w NaOH (1 ml) and water (3 ml). The layers were separated. The aqueous layer was extracted with EtOAc (3 x 10 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and the solvent was evaporated. The crude product was purified by flash column chromatography (eluting with a gradient of 0-100% EtOAc/Heptane) to give the title compound (10 mg, 22.4%) as a yellow oil.

HPLC MS (Method A): [m/z]: 252.95 [M+H] ^+.
N-(2-nitrophenyl)prop-2-enamide (D)

To a stirred suspension of 2-nitroaniline (5.0 g, 36.2 mmol) and K ₂ CO ₃ (15.01 g, 108.6 mmol) in acetone (100 ml) was added acryloyl chloride (11.8 ml, 145 mmol) at room temperature. Was added and the mixture was stirred for 16 hours. The reaction mixture was filtered and concentrated in vacuo to give crude product. Purification by flash column chromatography (gradient elution 10-15% EtOAc/heptane) provided the title compound (6.95 g, 78%) as a yellow solid.

_{1H-NMR (CDCl 3, 250MHz} ): d [ppm] = 10.59 (s, 1H), 8.90 (dd, J = 8.6,1.3Hz, 1H), 8.25 (dd, J =8.5, 1.6Hz, 1H), 7.68 (ddd, J = 8.5, 7.3, 1.4Hz, 1H), 7.21 (ddd, J = 8.6, 7.3). , 1.4 Hz, 1 H), 6.54-6.28 (m, 2 H), 5.89 (dd, J=9.9, 1.3 Hz, 1 H)
HPLC MS (Method A): [m/z]: 192.9 [M+H] ^+.
2-(chloromethyl)-5-(trifluoromethyl)-1H-1,3-benzodiazole (E)

12M HCl (1 ml, 12 mmol) in a mixture of 4-(trifluoromethyl)benzene-1,2-diamine (1 g, 5.68 mmol) and chloroacetic acid (0.590 g, 6.25 mmol) in water (20 ml). Addition and the mixture was heated at 100° C. for 2 hours. Further 12M HCl (4 ml, 48 mmol) was added and the reaction mixture was heated at 120° C. for 3 hours. The mixture was then cooled to room temperature, quenched by addition of 7M ammonia in MeOH until basic, extracted with EtOAc (3×20 ml), the combined organic layers were washed with brine (20 ml) and dried. (MgSO _4), filtered and evaporated in vacuo. Flash column chromatography (gradient elution with 5-50% EtOAc/heptane) gave the crude title compound as a purple solid (0.571 g, 24%, 56% pure), which was used without further purification.

HPLC MS (Method E): [m/z]: 234.85 [M+H] ^+.
tert-Butyl 2-(chloromethyl)methyl-1H-1,3-benzodiazole-1-carboxylate (F)

To a solution of 2-(chloromethyl)-6-methyl-1H-1,3-benzodiazole (1 g, 6 mmol) in DMF (20 ml) was added DIPEA (1.4 g, 11 mmol) followed by Boc anhydride. (1.8 g, 8 mmol) was added. The reaction was stirred for 18 hours. Water was added to the reaction and extracted with ethyl acetate. The organic phase is dried over Na ₂ SO ₄ and concentrated in vacuo to give a crude product which is flash column chromatographed using n-hexane-ethyl acetate/n-hexane (5:95)-hexane. Purified by to give the required product as a yellow oil (0.7 g, 22%). The required products were obtained as a mixture, which could not be separated and used for the next step.

_{1H-NMR (CDCl 3, 400MHz} ): d [ppm] = 7.84 (d, J = 8.7Hz, 2H), 7.62 (d, J = 8.2Hz, 1H), 7.53 (s , 1H), 7.20 (dd, J=13.0, 4.6 Hz, 2H), 5.05 (s, 2H), 5.04 (s, 2H), 2.50 (s, 3H), 2.47 (s, 3H), 1.74 (s, 9H), 1.73 (s, 9H),
N-(3-Fluoro-2-nitrophenyl)prop-2-enamide (G)

3-fluoro-2-nitroaniline (500 mg, 3.20 mmol) and _{K 2 CO 3 (1.33g, 9.61mmol} ) in the middle of acetone (10 ml) _{N 2} purge suspension, prop-2-Enoirukurorido (1.0 ml, 12.8 mmol) was added. The reaction mixture was left stirring at room temperature for 16 hours. The reaction was filtered, concentrated in vacuo and purified by flash column chromatography (eluting with a gradient of 0-70% EtOAc/heptane) to give the title compound (604 mg, 87%) as a yellow solid.

1H-NMR (DMSO-d6, 250MHz): d[ppm] = 10.58 (s, 1H), 7.69 (m, 1H), 7.46-7.33 (m, 2H), 6.43. (Dd, J=17.0, 9.8 Hz, 1H), 6.27 (dd, J=17.0, 2.1 Hz, 1H), 5.85 (dd, J=9.8, 2.1 Hz) , 1H)
HPLCMS (Method A): [m/z]: 210.95 [M+H] ^+.
N-(3-chloro-2-nitrophenyl)prop-2-enamide (H)

Acryloyl chloride (1.03 ml, 12.67 mmol) was suspended in 3-chloro-2-nitroaniline (0.729 g, 4.22 mmol) and K ₂ CO ₃ (2.34 g, 16.9 mmol) in acetone (20 ml). Slowly added to the suspension. The reaction mixture was stirred at room temperature for 4 hours, filtered and the residue rinsed with acetone. The combined filtrate was evaporated in vacuo. Purification by flash column chromatography (eluting with a gradient of 0-60% EtOAc/heptane) gave the title compound (0.52 g, 47%) as a yellow solid.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.36 (dd, J=8.3, 1.1 Hz, 1H), 8.28 (s, 1H), 7.49 (dd, J). =8.3, 8.3 Hz, 1H), 7.32 (dd, J=8.3, 1.1 Hz, 1H), 6.47 (dd, J=16.9, 0.8 Hz, 1H), 6.25 (dd, J=16.9, 10.3 Hz, 1H), 5.90 (dd, J=10.3, 0.8 Hz, 1H)
HPLC MS (method M): [m/z]: 227.00 [M+H] ^+.
N-(2-methoxy-6-nitrophenyl)prop-2-enamide (I)

2-methoxy-6-nitroaniline (0.52 g, 3.09 mmol) and _{K 2 CO 3 (1.71g, 12.4mmol} ) in the middle of acetone (30 ml) _{N 2} purge stirred suspension of acryloyl chloride (0 0.754 ml, 9.28 mmol) was added dropwise. The reaction mixture was left stirring at room temperature for 16 hours. The mixture was filtered, concentrated, diluted with EtOAc, washed with water, dried (MgSO _4), filtered, and concentrated to give the crude product. Purification by flash column chromatography (0-100% EtOAc/heptane, followed by elution with a gradient of 0-2% MeOH/EtOAc) gave the title compound (0.674 g, 96%) as an orange solid.

1H-NMR (CDCl ₃ , 250 MHz): d[ppm]=7.82 (s, 1H), 7.57 (dd, J=8.2, 1.3 Hz, 1H), 7.31 (t, J). =8.3 Hz, 1 H), 7.19 (dd, J=8.3, 1.3 Hz, 1 H), 6.47 (dd, J=17.0, 1.7 Hz, 1 H), 6.33 ( dd, J=17.0, 9.8 Hz, 1H), 5.85 (dd, J=9.8, 1.7 Hz, 1H), 3.97 (s, 3H)
HPLC MS (method M): [m/z]: 223.05 [M+H] ⁺
N-(5-fluoro-2-nitrophenyl)prop-2-enamide (J)

Acryloyl chloride (3.8 ml, 46.5 mmol) and 5-fluoro-2-nitroaniline (2.4 g, 15.5 mmol) and _{K 2 CO 3 (8.57g, 62mmol} ) Medium acetone (100ml) suspension of The mixture was stirred slowly at room temperature for 3 days and at reflux for 6 hours. Further acryloyl chloride (3.8 ml, 46.5 mmol) and DMAP (0.95 g, 7.75 mmol) were added and the mixture was heated at reflux for a further 2 hours. The reaction mixture was cooled to room temperature and filtered. The residue was rinsed with acetone and the combined filtrate was evaporated under vacuum. The resulting residue was redissolved in Et ₂ O (350 ml) and saturated NaHCO ₃ (aq) (200 ml). The mixture was vigorously stirred for 15 minutes. The phases were separated and the organic phase was washed with more saturated NaHCO ₃ (aq) (100 ml) and brine (100 ml), dried (sodium sulphate) and evaporated under vacuum. Purification by running through a silica plug (eluting with a gradient of 0-4% Et ₂ O/heptane) gave the title compound (1.04 g, 32%) as a pale yellow solid.

_{1H-NMR (CDCl 3, 250MHz} ): d [ppm] = 10.83 (s, 1H), 8.79 (dd, J = 11.2,2.5Hz, 1H), 8.34 (dd, J =9.2, 5.7 Hz, 1H), 6.99-6.82 (m, 1H), 6.53 (d, J=16.9 Hz, 1H), 6.35 (dd, J=17. 1,9.9Hz, 1H), 5.95 (d, J=10.1Hz, 1H)
HPLC MS (Method M): [m/z]: 211.15 [M+H] ^+.
General Scheme KI above:
N-(2-chloro-5-fluorophenyl)prop-2-enamide (K1)

To a N ₂ purge suspension of 2-chloro-5-fluoroaniline (3.0 g, 20.6 mmol) and K ₂ CO ₃ (11.4 g, 82.4 mmol) in acetone (80 ml) was added propa-2 at room temperature. -Enoyl chloride (5.0 ml, 61.8 mmol) was added dropwise and stirred for 16 hours. The reaction mixture was filtered, concentrated in vacuo and purified by flash column chromatography (eluting with a gradient of 0-35% EtOAc/heptane) to give the title compound (3.99 g, 84%) as a white solid. ..

1H-NMR (CDCl ₃ , 250 MHz): d[ppm]=8.40 (dd, J=10.9, 3.0 Hz, 1H), 7.79 (s, 1H), 7.35 (dd, J). =8.9, 5.6 Hz, 1H), 6.81 (ddd, J=8.9, 7.6, 3.0 Hz, 1H), 6.50 (dd, J=16.9, 1.2 Hz) , 1H), 6.32 (dd, J=16.9, 10.0 Hz, 1H), 5.88 (dd, J=10.0, 1.2 Hz, 1H)
HPLCMS (Method A): [m/z]: 200.10 [M+H] ^+.
N-(6-chloro-3-fluoro-2-nitrophenyl)prop-2-enamide (K2)

N-(2-chloro-5-fluorophenyl) prop-2-enamide (K1) (3.99g, 17.4mmol) , the _{N 2} purge solution of concentrated _H 2 _SO 4 (15ml) and AcOH (6 ml), Red fuming HNO ₃ (1.8 ml, 38.3 mmol) was added dropwise at 0° C. and the reaction was left stirring for 2 h. The reaction mixture was poured into ice water and extracted with DCM (4 x 40 ml). The combined organic extracts were dried (MgSO ₄ ), filtered, concentrated in vacuo and purified by flash column chromatography (eluting with a gradient of 0-70% EtOAc/heptane) to give the title compound (1.08 g, 20%) was obtained as a white solid.

1H-NMR (CDCl ₃ , 250 MHz): d[ppm]=7.64 (dd, J=9.1, 5.0 Hz, 1H), 7.51 (s, 1H), 7.19 (m, 1H). ), 6.52 (dd, J=16.9, 1.1 Hz, 1H), 6.32 (dd, J=16.9, 10.2 Hz, 1H), 5.94 (dd, J=10. 1,1.1Hz, 1H)
HPLCMS (Method A): [m/z]: 244.95 [M+H]+
N-(2,4-difluorophenyl)prop-2-enamide (K3)

2,4-difluoroaniline (2 g, 1.49 mmol) and _{K 2 CO 3 (8.56g, 61.7mmol} ) in the middle of acetone (60 ml) _{N 2} purge suspension, prop at room temperature 2-Enoirukurorido (3.7 ml, 46.5 mmol) was added dropwise. The reaction mixture was left stirring for 16 hours. The reaction was filtered, concentrated, purified by flash column chromatography (eluting with a gradient of 0-30% EtOAc/heptane) and triturated with heptane to give the title compound (2.9 g, 100%) as a white solid. Was obtained.

1H-NMR (CDCl ₃ , 250 MHz): d [ppm] = 8.49-8.29 (m, 1H), 7.33 (s, 1H), 6.99-6.84 (m, 2H), 6.48 (dd, J=16.9, 1.4 Hz, 1H), 6.29 (dd, J=16.8, 10.1 Hz, 1H), 5.85 (dd, J=10.1, 1.4Hz, 1H)
HPLC MS (Method A): [m/z]: 183.95 [M+H] ^+.
N-(2,4-difluoro-6-nitrophenyl)prop-2-enamide (K4)

N-(2,4-difluorophenyl) prop-2-enamide (K3) (2.9g, 15.4mmol) , the _{N 2} purge solution of AcOH (5 ml) and concentrated _{H 2 SO 4 (13ml),} 0 ℃ Red fuming nitric acid (1.6 ml) was added dropwise. The reaction mixture was left stirring for 2 hours. The reaction was poured into ice water and the resulting solution was extracted with DCM (4 x 40 ml). The combined organic extracts were washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo was triturated with heptane to give the crude product as a beige solid (3.23 g). Purification by flash column chromatography (eluting with a gradient of 0-40% EtOAc/heptane) gave the title compound (1.25 g, 35.5%) as a white solid.

1H-NMR (CDCl ₃ , 250 MHz): d[ppm]=8.17 (s, 1H), 7.67 (dt, J=7.9, 2.4 Hz, 1H), 7.34-7.28. (M, 1H), 6.51 (dd, J=17.0, 1.4 Hz, 1H), 6.35 (dd, J=17.0, 9.9 Hz, 1H), 5.92 (dd, J=9.9, 1.3Hz, 1H)
HPLC MS (Method A): [m/z]: 229.05 [M+H]+.
N-(2,5-difluorophenyl)prop-2-enamide (K5)

2,5-difluoroaniline (1.5 ml, 15.5 mmol) and _{K 2 CO 3 (6.42g, 46.5mmol} ) in the middle of acetone (60 ml) _{N 2} purge stirred solution of prop at room temperature 2-enoyl Chloride (5.0 ml, 61.96 mmol) was added dropwise. The reaction mixture was left stirring at room temperature for 2 hours. The reaction was filtered and the filtrate was concentrated to give a white solid which was triturated with heptane to give the title compound (2.91 g, quant.) as a white solid.

_{1H-NMR (CDCl 3, 250MHz} ): d [ppm] = 8.30 (m, 1H), 7.50 (s, 1H), 7.07 (m, 1H), 6.85-6.70 ( m, 1H), 6.50 (dd, J=16.8, 1.2 Hz, 1H), 6.30 (dd, J=16.9, 10.1 Hz, 1H), 5.87 (dd, J = 10.1, 1.2Hz, 1H)
HPLC MS (Method A): [m/z]: 183.95 [M+H] ^+.
N-(3,6-difluoro-2-nitrophenyl)prop-2-enamide (K6)

N-(2,5-difluorophenyl) prop-2-enamide (K5) (2.91g, 15.9mmol) , the _{N 2} purge stirred solution of AcOH (5 ml) and concentrated _{H 2 SO 4 (13ml),} 0 Red fuming HNO ₃ (1.6 ml, 34.0 mmol) was added dropwise at °C. The reaction mixture was left stirring for 2 hours. The reaction was poured into ice water and the resulting solution was extracted with DCM (4 x 40 ml). The combined organic extracts were washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo. Purification by flash column chromatography (eluting with a gradient of 0-60% EtOAc/heptane) followed by flash column chromatography (eluting with a gradient of 20% EtOAc/heptane) gave the title compound (0.316 g, 8%). Obtained as a white solid.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=7.64 (s, 1H), 7.39 (m, 1H), 7.19 (m, 1H), 6.51 (dd, J= 17.0, 0.7 Hz, 1H), 6.32 (dd, J=17.0, 10.4 Hz, 1H), 5.93 (dd, J=10.4, 0.7 Hz, 1H)
HPLCMS (Method A): [m/z]: 228.95 [M+H] ^+.
N-[2-(trifluoromethyl)phenyl]prop-2-enamide (K7)

To a N ₂ purge suspension of 2-(trifluoromethyl)aniline (3.1 ml, 24.83 mmol) and K ₂ CO ₃ (10.3 g, 74.48 mmol) in acetone (90 ml) was added prop-2-e. Noyl chloride (8.0 ml, 99.30 mmol) was added dropwise. The reaction mixture was left stirring at room temperature for 3 hours. The reaction was filtered, concentrated in vacuo and triturated with heptane to give the title compound (4.74g, 86%) as a white solid.

_{1H-NMR (CDCl 3, 250MHz} ): d [ppm] = 8.34 (d, J = 8.2Hz, 1H), 7.70-7.45 (m, 3H), 7.28-7.22 (M, 1H), 6.46 (dd, J=16.9, 1.3 Hz, 1H), 6.29 (dd, J=16.9, 10.0 Hz, 1H), 5.86 (dd, J=10.0, 1.3Hz, 1H)
HPLCMS (Method A): [m/z]: 215.90 [M+H] ^+.
N-[2-nitro-6(trifluoromethyl)phenyl]prop-2-enamide (K8)

N- [2- (trifluoromethyl) phenyl] prop-2-enamide (K7) (4.64g, 20.91mmol) , the _{N 2} purge solution of AcOH (5 ml) and concentrated _H 2 _SO 4 (13ml), Red fuming HNO ₃ (1.6 ml, 34.05 mmol) was added dropwise at 0°C. The reaction mixture was left stirring at room temperature for 16 hours. The reaction was poured into ice water then extracted with DCM (4 x 40 ml). Dry the organic extracts combined (MgSO _4), filtered, and concentrated in vacuo. Purification by flash column chromatography (eluting with a gradient of 0-20% EtOAc/heptane) gave the title compound (0.829 g, 12%) as a beige solid.

HPLCMS (Method A): [m/z]: 260.95 [M+H] ^+.
N-(2,3-difluorophenyl)prop-2-enamide (K9)

To a solution of 2,3-difluoroaniline (3 ml, 31 mmol) and K ₂ CO ₃ (12.9 g, 92.9 mmol) in N ₂ purge in acetone (120 ml) was added prop-2-enoyl chloride (10 ml, 124 mmol) at room temperature. ) Was added dropwise. The reaction mixture was left stirring for 16 hours. The reaction was filtered and the filtrate was concentrated to give a white solid which was triturated from heptane to give the title compound (4.97g, 87%) as a white solid.

_{1H-NMR (CDCl 3, 250MHz} ): d [ppm] = 8.29-8.12 (m, 1H), 7.46 (s, 1H), 7.18-7.04 (m, 1H), 7.02-6.85 (m, 1H), 6.50 (dd, J=16.8, 1.3 Hz, 1H), 6.31 (dd, J=16.9, 10.1 Hz, 1H) , 5.87 (dd, J=10.1, 1.3Hz, 1H)
HPLC MS (Method A): [m/z]: 184.2 [M+H] ^+.
N-(2,3-difluoro-6-nitrophenyl)prop-2-enamide (K10)

N-(2,3-difluorophenyl) prop-2-enamide (K9) (4.9g, 26.8mmol) , the _{N 2} purge solution of AcOH (5 ml) and concentrated _{H 2 SO 4 (13ml),} 0 ℃ Nitric acid (1.6 ml) was added dropwise. The reaction mixture was left stirring for 2 hours. The reaction was poured into ice/water and the solution was extracted with DCM (5x30ml). The combined organic extracts were washed with brine (50ml), dried over MgSO _4, filtered, and concentrated to give the crude product. This was triturated with heptane (100 ml). The suspension was filtered and the residue was collected to give a mixture of both para/ortho-nitrated regioisomers as a beige solid (6g). Purification by acidic preparative HPLC gave the title compound (4.2 g) as a white solid.

HPLCMS (Method A): [m/z]: 228.95 [M+H] ^+.
General Scheme K-II above:
N-(4-cyanophenyl)prop-2-enamide (K11)

Acryloyl chloride (0.69 ml, 8.46 mmol) was added 4-aminobenzonitrile (250 mg, 2.12 mmol) and _{K 2 CO 3 (880mg, 6.35mmol} ) in an ice-cold suspension of acetone (5ml) of .. The mixture was stirred for 18 hours while warming to room temperature. The reaction mixture was filtered and the residue was rinsed with acetone (5 ml). The combined filtrate was evaporated in vacuo and crude purification by flash column chromatography with elution gradient 0-80% EtOAc/heptane gave the title compound (353 mg, 96%) as a white solid.

_{1H-NMR (CDCl 3, 250MHz} ): d [ppm] = 7.73 (d, J = 8.8Hz, 2H), 7.68-7.58 (m, 2H), 7.37 (s, 1H ), 6.49 (dd, J=16.8, 1.0 Hz, 1H), 6.25 (dd, J=16.8, 10.2 Hz, 1H), 5.86 (dd, J=10. 2, 1.0Hz, 1H)
HPLC MS (Method M): [m/z]: 173.45 [M+H] ^+.
N-(4-cyano-2-nitrophenyl)prop-2-enamide (K12)

Nitric acid (0.6 ml) was added dropwise to an ice-cold solution of N-(4-cyanophenyl)prop-2-enamide (K11) (1.03 g, 5.75 mmol) in acetic acid (2 ml) and sulfuric acid (4.75 ml). Added The reaction mixture was stirred for 3 hours then poured into ice cold water and the mixture was extracted with DCM (4 x 20 ml). Dry the organic extracts combined (MgSO _4), and evaporated in vacuo. Purification by flash column chromatography using elution gradient 0-90% EtOAc/heptane gave the title compound (1.2 g, 93%) as a yellow solid.

_{1H-NMR (CDCl 3, 250MHz} ): d [ppm] = 10.77 (s, 1H), 9.14 (d, J = 8.9Hz, 1H), 8.58 (d, J = 2.0Hz , 1H), 7.90 (dd, J=8.9, 1.7 Hz, 1H), 6.54 (dd, J=17.0, 0.9 Hz, 1H), 6.35 (dd, J= 17.0, 10.1Hz, 1H), 5.98 (dd, J=10.1, 0.9Hz, 1H)
tert-Butyl 2-(chloromethyl)-1H-1,3-benzodiazole-1-carboxylate (L)

2-(Chloromethyl)-1H-1,3-benzodiazole (10 g, 0.06 mol), BOC ₂ O (18 ml, 0.06 mol) and TEA (6.07 g, 0.06 mol) in DCM (304 ml). The medium mixture was cooled to 0°C. A catalytic amount of DMAP (0.73 g, 0.006 mol) was added and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc (150 ml), washed with saturated NaHCO ₃ (150 ml), brine (150 ml), dried (Na ₂ SO ₄ ), filtered and concentrated to give crude product. Purification by flash column chromatography (eluting with a gradient of 5-10% EtOAc/heptane) gave the title compound (7 g, 44%) as an off-white oil.

HPLC MS (Method H): [m/z]: 167.2 [M-Boc+H] ^+.
General Scheme I-1 above:
Ethyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-4-methyl-1,3-thiazole-5-carboxylate (208)

In a manner similar to General Procedure 1, tert-butyl(3-amino-3-thioxopropyl)carbamate (1.0 g, 5.34 mmol), CaCO ₃ (0.29 g, 2.93 mmol) and ethyl 2-. A suspension of chloro-3-oxobutanoate (0.81 ml, 5.86 mmol) in EtOH (15 ml) was heated at 60° C. for 18 hours. The reaction was cooled to room temperature and concentrated in vacuo. The residue was partitioned between EtOAc and water and the phases separated. The aqueous phase was extracted with EtOAc (2 x 80ml) and the combined organic extracts washed with brine (80ml). The organic phase was dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. Purification by flash column chromatography (eluting with a gradient of 5-50% EtOAc/heptane) provided the title compound (1.57 g, 94%) as a white solid.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=5.01 (br s, 1H), 4.34 (q, J=7.1 Hz, 2H), 3.57 (dt, J=5. 5,5.5 Hz, 2H), 3.15 (t, J=6.3 Hz, 2H), 2.73 (s, 3H), 1.47 (s, 9H), 1.38 (t, J= 7.1Hz, 3H)
HPLC MS (Method A): [m/z]: 315.10 [M+H] ^+.
Ethyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-5-carboxylate (209)

In a manner similar to General Procedure 1, tert-butyl N-(2-carbamothioylethyl)carbamate (1 g, 4.89 mmol), calcium carbonate (0.27 g, 3 mmol) and ethyl 2-chloro-3-oxo. Propanoate (0.81 g, 5 mmol) was combined in EtOH (15 ml) and the mixture heated at 60° C. for 18 hours. Further 2-chloro-3-oxopropanoate (0.81 g, 5 mmol) was added and the mixture was further heated at 80° C. for 5 hours. The reaction was cooled to room temperature and concentrated in vacuo. The residue was partitioned between water and EtOAc and the mixture was extracted with EtOAc (3x80ml). The combined organic extracts were washed with brine (80 ml), dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. Purification by flash column chromatography (eluting with a gradient of 20-60% EtOAc/heptane) gave the crude title compound (743 mg) as a brown oil, which was used in the next step without further purification.

HPLCMS (Method A): [m/z]: 301.05 [M+H] ^+.
2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-4-methyl-1,3-thiazole-5-carboxylic acid (210)

In a manner similar to general procedure 5, ethyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-4-methyl-1,3-thiazole- in THF (30 ml) and water (15 ml). 5-Carboxylate (208) (1.57 g, 4.99 mmol) and LiOH (0.72 g, 30 mmol) gave the title compound (1.23 g, 86%) as a white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=6.99 (t, J=5.3 Hz, 1H), 3.28 (m, 2H), 3.04 (t, J=6. 7Hz, 2H), 2.58 (s, 3H), 1.37 (s, 9H)
HPLC MS (Method A): [m/z]: 287.05 [M+H] ^+.
2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-5-carboxylic acid (211)

In a manner similar to General Procedure 5, crude ethyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-5-carboxy in THF (20 ml) and water (10 ml). The rate (209) (743 mg, 2.47 mmol) and LiOH (300 mg, 12 mmol) gave the crude title compound (500 mg) as a brown oil which was used in the next step without further purification.

HPLCMS (Method A): [m/z]: 273.05 [M+H] ^+.
tert-Butyl N-[2-(5-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-4-methyl-1,3-thiazol-2-yl)ethyl]carbamate (212)

In a manner similar to general procedure 6, 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-4-methyl-1,3-thiazole-5-carboxylic acid (210) in DCM (20 ml). ) (0.457 g, 1.6 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (0.349 g, 1.76 mmol), DIPEA (0.92 ml, 5 mmol) and HATU(0. 0.73 g, 2 mmol) gave the crude title compound (1.26 g) as a colorless oil.

HPLC MS (Method A): [m/z]: 395.1 [M+H] ^+.
tert-Butyl N-[2-(5-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (213)

In a manner similar to general procedure 6 crude 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-5-carboxylic acid (211) (500 mg) in DCM (30 ml). ), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (402 mg, 2.02 mmol), DIPEA (1.06 ml, 6 mmol) and HATU (840 mg, 2 mmol) by flash column chromatography (20. The crude title compound (953 mg, 87% pure) was obtained as a yellow residue after partial purification by elution with -100% EtOAc/Heptane followed by a gradient of 0-10% MeOH/EtOAc.

HPLC MS (Method A): [m/z]: 381.05 [M+H] ^+.
2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-4-methyl-1,3-thiazol-5-carboxamide (214)

In a manner similar to general procedure 2, crude tert-butyl N-[2-(5-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-4-methyl-1, in MeOH (20 ml). 3-Thiazol-2-yl)ethyl]carbamate (212) (1.26 g) and 12M HCl (2 ml), purified with SCX-2 cartridge, rinsed with DCM and MeOH, then with 7N ammonia in MeOH. After elution, the title compound free base (471 mg) was obtained as a white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.56 (t, J=5.5 Hz, 1H), 8.39 (dt, J=4.6, 1.3 Hz, 1H), 7.73-7.67 (m, 1H), 7.43-7.38 (m, 1H), 4.61-4.56 (m, 2H), 3.03 (t, J=7.0Hz). , 2H), 2.95 (t, J=6.5 Hz, 2H), 2.54 (s, 3H)
HPLCMS (Method A): [m/z]: 295.05 [M+H] ^+.
2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (215)

In a manner similar to General Procedure 2, crude tert-butyl N-[2-(5-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazole- in MeOH (20 ml). 2-yl)ethyl]carbamate (213) (87%, 923 mg, 2.11 mmol) and 12M HCl (2 ml), purified with SCX-2 cartridge, rinsed with DCM and MeOH, then 7N ammonia in MeOH. After eluting with, the title compound free base (389 mg) was obtained as a yellow residue.

HPLCMS (Method A): [m/z]: 280.95 [M+H] ^+.
2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-4-methyl -1,3-thiazole-5-carboxamide (Example compound No. 7)

In a manner similar to General Procedure 8, 2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-4-methyl-1,3-thiazol-5-carboxamide (214 ) (471 mg, 1.6 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (295 mg, 1.54 mmol) and DBU (0.26 ml, 2 mmol) gave the crude intermediate, which Was further reacted with iron powder (280 mg, 5 mmol) in AcOH (5 ml) to give the title compound after purification by basic preparative HPLC followed by flash column chromatography (eluting with a gradient of 0-30% MeOH/DCM). (115 mg, 20%) was obtained as a white solid.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.38 (d, J=4.7Hz, 1H), 7.61(t, J=9.2Hz, 1H), 7.52- 7.46 (m, 2H), 7.43-7.38 (m, 1H), 7.22-7.15 (m, 2H), 4.73 (s, 2H), 3.22-3. 14 (m, 4H), 3.14-3.05 (m, 4H), 2.51 (s, 3H)
HPLC MS (Method C): [m/z]: 439.1 [M+H] ^+.
2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3 -Thiazole-5-carboxamide (Example compound No. 8)

In a similar manner to General Procedure 8, 2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide (MeCN (15 ml) in 15 ml). 215) (389 mg, 1.39 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (267 mg, 1.39 mmol) and DBU (0.25 ml, 2 mmol) gave the crude intermediate, This was further reacted with iron powder (230 mg, 4 mmol) in AcOH (5 ml) to give the title compound (49 mg, 11%) as a white solid after 3 purifications by basic preparative HPLC.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.38 (dt, J=4.9, 1.3Hz, 1H), 8.14(s, 1H), 7.65-7. 59 (m, 1H), 7.52-7.47 (m, 2H), 7.44-7.39 (m, 1H), 7.21-7.17 (m, 2H), 4.75 ( d, J=1.6 Hz, 2H), 3.23 (t, J=6.8 Hz, 2H), 3.15-3.07 (m, 6H)
HPLCMS (Method C): [m/z]: 425.1 [M+H] ^+.
General scheme 24 above:
Methyl 3-amino-2-hydroxypropanoate hydrochloride (332)

Thionyl chloride (1.8 ml, 20 mmol) was added dropwise to ice cold MeOH (60 ml) and stirred for 5 minutes. 3-Amino-2-hydroxypropanoic acid (1.04 g, 9.9 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was rigorously evaporated in vacuo to give the title compound (1.54g, quantitative) as a yellow oil.

1H-NMR (DMSO-d6, 250MHz): d [ppm] = 8.12 (s, 3H), 6.36 (s, 1H), 4.39 (dt, J = 8.8, 4.6Hz, 1H), 3.69 (s, 3H), 3.24-3.05 (m, 1H), 3.00-2.84 (m, 1H)
Methyl 3-(3-{[(tert-butoxy)carbonyl]amino}propanamide)-2-hydroxypropanoate (333)

In a similar manner to general procedure 13, methyl 3-amino-2-hydroxypropanoate hydrochloride (332) (4.35 g, 27.96 mmol) in DCM (80 ml), 3-{[(tert-butoxy). Carbonyl]amino}propanoic acid (5.82 g, 30.76 mmol), TEA (4.68 ml, 34 mmol) and DCC (5.77 g, 28 mmol) by flash column chromatography (gradient 0-100% EtOAc/heptane). After purification, the title compound (5.12 g, 63%) was obtained as a pale yellow oil.

_{1H-NMR (CDCl 3, 500MHz} ): d [ppm] = 6.06 (s, 1H), 5.18 (s, 1H), 4.32 (q, J = 4.9Hz, 1H), 3. 83 (s, 3H), 3.72-3.60 (m, 2H), 3.46 (d, J=5.4Hz, 1H), 3.45-3.38 (m, 2H), 2. 47-2.36 (m, 2H), 1.46 (s, 9H)
HPLCMS (Method A): [m/z]: 313.00 [M+Na] ^+.
Methyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-4,5-dihydro-1,3-oxazole-5-carboxylate (334)

In a manner similar to general procedure 14, methyl 3-(3-{[(tert-butoxy)carbonyl]amino}propanamide)-2-hydroxypropanoate (333) (3.63 g, in DCM (100 ml)). 12.5 mmol), DAST (1.98 ml, 15 mmol) and _K by 2 _CO 3 (3.46 g, 25 mmol), after purification by flash column chromatography (eluting with a gradient of 40 to 100% EtOAc / heptane) to give the title compound (3.4 g, 99%) was obtained as a colorless oil.

_{1H-NMR (CDCl 3, 250MHz} ): d [ppm] = 4.96 (dd, J = 10.8,6.5Hz, 1H), 4.24-4.09 (m, 1H), 4.04 -3.88 (m, 1H), 3.83 (s, 3H), 3.58-3.38 (m, 2H), 2.57 (d, J=4.8Hz, 2H), 1.47. (S, 9H)
HPLC MS (Method M): [m/z]: 272.95 [M+H] ^+.
General Procedure 16: Methyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-oxazole-5-carboxylate (335).

Methyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-4,5-dihydro-1,3-oxazole-5-carboxylate (334) (3.2 g, 11.75 mmol), NBS A solution of (2.3 g, 12.93 mmol) and AIBN (0.19 g, 1.18 mmol) in DCE (30 ml) was heated at 80° C. for 1.5 hours. The reaction mixture was cooled to room temperature, quenched with saturated NaHCO ₃ (aq) and extracted with DCM (3×80 ml). Dry the organic extracts combined _(Na 2 _SO 4), filtered and evaporated in vacuo. Purification by flash column chromatography (eluting with a gradient of 0-80% EtOAc/heptane) gave the crude title compound (1.25 g, 29%, 75% pure) as an orange residue. The compound was used in the next step without further purification.

1H-NMR (CDCl ₃ , 250 MHz): d[ppm]=7.69 (s, 1H), 5.17-4.98 (m, 1H), 3.94 (s, 3H), 3.62 ( q, J=6.2 Hz, 2H), 3.05 (t, J=6.2 Hz, 2H), 1.46 (s, 9H)
HPLC MS (Method M): [m/z]: 271.00 [M+H] ^+.
2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-oxazole-5-carboxylic acid (336)

In a manner similar to General Procedure 5, crude methyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-oxazole-5-carboxy in THF (20 ml) and water (20 ml). The rate (335) (1.24 g, 3.44 mmol, purity 75%) and LiOH (0.329 mg, 13.76 mmol) gave the title compound (0.51 g, 44%) as a pale orange residue. The compound was used in the next step without further purification.

1H-NMR (CDCl ₃ , 250 MHz): d[ppm]=7.76 (s, 1H), 5.14 (s, 1H), 3.71-1.56 (m, 2H), 3.09( t, J=6.2 Hz, 2H), 1.46 (s, 9H)
HPLC MS (Method M): [m/z]: 256.95 [M+H] ^+.
tert-Butyl N-[2-(5-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-oxazol-2-yl)ethyl]carbamate (337)

In a similar manner to General Procedure 6 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-oxazole-5-carboxylic acid (336) (513 mg, in DCM (20 ml). 2 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (479 mg, 2.4 mmol), DIPEA (1.15 ml, 6.61 mmol) and HATU (837 mg, 2.2 mmol) crude. The title compound (1.08 g, 74%, 50% purity) was obtained as a yellow residue. The compound was used in the next step without purification.

HPLC MS (method M): [m/z]: 365.05 [M+H] ⁺
2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-5-carboxamide (338)

In a manner similar to General Procedure 2, crude tert-butyl N-[2-(5-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-oxazole- in MeOH (10 ml). 2-yl)ethyl]carbamate (337) (1.08 g, 1.48 mmol) and 12M HCl (1 ml), free basified using SCX-2 cartridge (10 g), rinsed with DCM and MeOH, then MeOH. After eluting with 7N ammonia in, the title compound free base (444 mg, 57%) was obtained as a pale yellow solid.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.99 (t, J=5.7 Hz, 1H), 8.39 (dt, J=4.6, 1.5 Hz, 1H), 7.78-7.64 (m, 2H), 7.48-7.36 (m, 1H), 4.61 (dd, J=5.8, 1.6Hz, 2H), 3.07-2. .86 (m, 4H)
HPLC MS (Method M): [m/z]: 264.95 [M+H] ^+.
2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3 -Oxazole-5-carboxamide (Example compound No. 1)

In a similar manner to General Procedure 8-2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-5-carboxamide (MeCN (10 ml)). 338) (444 mg, 1.68 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (323 mg, 1.68 mmol) and DBU (301 μl, 2.02 mmol) gave the crude intermediate, This was further reacted with iron powder (343 mg, 6.13 mmol) in AcOH (10 ml) after flash column chromatography (eluting with a gradient of 0-40% MeOH/DCM) followed by purification by basic preparative HPLC. The title compound was obtained as a pale yellow solid (166 mg, 25%).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.12 (s, 1H), 8.96 (t, J=5.8 Hz, 1H), 8.38 (dt, J=4. 6,1.4 Hz, 1H), 7.73-7.66 (m, 2H), 7.53-7.37 (m, 3H), 7.11 (dt, J=6.0, 3.5 Hz). , 2H), 4.61 (dd, J=5.7, 1.4 Hz, 2H), 3.04-2.89 (m, 8H).
HPLCMS (Method B): [m/z]: 409.1 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-5 Carboxamide (Example compound No. 4)

In a similar manner to General Procedure 3, 2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole in MeOH (10 ml) for 16 hours at room temperature. 5-carboxamide (338) (250mg, 0.83mmol, 88% purity), 1H-benzimidazol-2-carbaldehyde (170mg, 1.17mmol), DIPEA ( 0.44ml, 2.5mmol) and MgSO ₄ ( 150 mg, 1.25 mmol) gave the intermediate which was further reacted with NaBH ₄ (47 mg, 1.25 mmol) and flash column chromatography [0-5% (7N NH _{3 in} MeOH)/DCM gradient. After elution] with subsequent purification by basic preparative HPLC, the title compound (156 mg, 48%) was obtained as a white solid.

1H-NMR (DMSO-d6,500MHz): d[ppm]=12.17(brs,1H),8.95(t,J=5.8Hz,1H),8.39-8.34(m). , 1H), 7.72-7.65 (m, 2H), 7.54-7.46 (m, 1H), 7.46-7.36 (m, 2H), 7.17-7.06. (M, 2H), 4.63-4.56 (m, 2H), 3.93 (s, 2H), 3.02-2.94 (m, 4H), 2.57 (br s, 1H).
HPLC MS (Method D): [m/z]: 395.2 [M+H] ^+.
General Scheme 27 above:
tert-Butyl 3-[(2-hydroxy-3-methoxy-3-oxopropyl)carbamoyl]azetidine-1-carboxylate (354)

In a manner similar to general procedure 13 methyl 3-amino-2-hydroxypropanoate hydrochloride (2.9 g, 18.64 mmol) in DCM (80 ml), 1-(tert-butoxycarbonyl)azetidine-3-. By carboxylic acid (4.13 g, 20.5 mmol), TEA (5.45 ml, 39.14 mmol) and DCC (4.04 g, 19.57 mmol) flash column chromatography (0-100% EtOAc/heptane, followed by. After purification by elution with a gradient of 0-3% MeOH/EtOAc), the title compound (4.47 g, 79%) was obtained as a viscous pale yellow oil.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=5.92 (s, 1H), 4.32 (dd, J=5.3, 4.3 Hz, 1H), 4.14-4.03. (M, 5H), 3.84 (s, 3H), 3.74-3.63 (m, 2H), 3.24-3.14 (m, 1H), 1.46 (s, 9H).
HPLC MS (Method M): [m/z]: 325.00 [M+H] ^+.
Methyl 2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-4,5-dihydro-1,3-oxazol-5-carboxylate (355)

In a similar manner to general procedure 14 tert-butyl 3-[(2-hydroxy-3-methoxy-3-oxopropyl)carbamoyl]azetidine-1-carboxylate (354) (4.47 g) in DCM (100 ml). , 14.79 mmol) and DAST (2.15 ml, 16.26 mmol) followed by quenching with K ₂ CO ₃ (4.09 g, 29.57 mmol) for flash column chromatography (20-100% EtOAc/heptane, followed by quenching). After purification by elution with a 1% MeOH/EtOAc gradient), the title compound (1.61 g, 38%) was obtained as a pale yellow oil.

_{1H-NMR (CDCl 3, 250MHz} ): d [ppm] = 5.00 (dd, J = 10.8,6.7Hz, 1H), 4.27-4.08 (m, 5H), 4.00 (Ddd, J=14.7, 6.7, 1.0 Hz, 1H), 3.83 (s, 3H), 3.55-3.39 (m, 1H), 1.46 (s, 9H).
Methyl 2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-oxazole-5-carboxylate (356)

In a similar manner to General Procedure 16, methyl 2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-4,5-dihydro-in DCE (60 ml) for 1.5 hours at 80°C. Flash column chromatography with 1,3-oxazole-5-carboxylate (355) (1.61 g, 5.66 mmol), NBS (1.11 g, 6.23 mmol) and AIBN (0.11 g, 0.57 mmol). After purification by (eluting with a gradient of 0-80% EtOAc/heptane), the title compound (756 mg, 45%) was obtained as a pale yellow oil.

1H-NMR (CDCl ₃ , 250 MHz): d[ppm]=7.74 (s, 1H), 4.38-4.23 (m, 4H), 4.03-3.83 (m, 5H), 1.48 (s, 9H)
HPLC MS (Method M): [m/z]: 304.95 [M+H] ^+.
2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-oxazole-5-carboxylic acid (357)

In a manner similar to General Procedure 5, methyl 2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-oxazole-5-carboxylate in THF/water (20 ml/20 ml). (356) (750 mg, 2.66 mmol) and LiOH (382 mg, 15.94 mmol) gave the title compound (710 mg, 99%) as a pale yellow oil. The title compound was used in the next step without purification.

1H-NMR (CDCl ₃ , 250 MHz): d[ppm]=7.83 (s, 1H), 4.40-4.25 (m, 4H), 4.04-3.94 (m, 1H), 1.48 (s, 9H)
HPLCMS (Method M): [m/z]: 290.90 [M+H] ^+.
tert-Butyl 3-(5-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-oxazol-2-yl)azetidine-1-carboxylate (358)

In a similar manner to general procedure 6 2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-oxazole-5-carboxylic acid (357)(0) in DCM (30 ml). 0.74 g, 2.77 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (0.61 g, 3.04 mmol), DIPEA (1.59 ml, 9.13 mmol) and HATU (1. After purification by flash column chromatography (20-100% EtOAc/heptane, followed by a gradient of 2-10% MeOH/EtOAc) by 16 g, 3.04 mmol), the title compound (2.26 g, 45% pure). Was obtained as a pale yellow oil. The material was used in the next step without further purification.

1H-NMR (CDCl ₃ , 250 MHz): d[ppm]=8.44 (dt, J=4.8, 1.3 Hz, 1H), 7.72 (s, 1H), 7.60 (s, 1H). ), 7.53-7.42 (m, 1H), 7.38-7.31 (m, 1H), 4.84 (dd, J=4.8, 1.5Hz, 2H), 4.42. -4.24 (m, 4H), 4.06-3.91 (m, 1H), 1.49 (s, 9H)
HPLC MS (Method M): [m/z]: 377.05 [M+H] ^+.
2-(azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-5-carboxamide (359)

In a similar manner to General Procedure 2 tert-butyl 3-(5-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-oxazol-2-yl) in MeOH (20 ml). Free basification with azetidine-1-carboxylate (358) (45%, 2.26 g, 2.7 mmol) and 12M HCl (2 ml) using SCX-2 cartridge (10 g), rinsing with DCM and MeOH, then , Elution with 7N ammonia in MeOH afforded the title compound (644 mg, 86%) as a white solid.

1H-NMR (DMSO-d6,500MHz): d[ppm]=9.03(t, J=5.6Hz, 1H), 8.39(dt, J=4.5, 1.3Hz, 1H), 7.74 (s, 1H), 7.70 (ddd, J = 10.0, 8.4, 1.2Hz, 1H), 7.41 (dt, J = 8.6, 4.4Hz, 1H) , 4.63-4.60 (m, 2H), 4.11-4.02 (m, 1H), 3.85 (t, J=7.6Hz, 2H), 3.78 (t, J=). 8.2Hz, 2H)
HPLC MS (method M): [m/z]: 276.95 [M+H] ^+.
2-{1-[2-(1H-1,3-benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-[(3-fluoropyridin-2-yl)methyl]-1, 3-Oxazole-5-carboxamide (Example compound No. 2)

In a similar manner to general procedure 8, 2-(azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-5-carboxamide in MeCN (10 ml). (359) (255 mg, 0.92 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (186 mg, 0.97 mmol) and DBU (145 μl, 0.97 mmol) gave the crude intermediate. , Which was further reacted with iron powder (167 mg, 3 mmol) in AcOH (4 ml), after purification by basic preparative HPLC followed by flash column chromatography (eluting with a gradient of 0-40% MeOH/DCM), The title compound (140 mg, 44%) was obtained as a white solid.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.36 (dt, J=4.7, 1.2 Hz, 1H), 7.69 (s, 1H), 7.62 (ddd, J=) 9.8, 8.4, 1.2 Hz, 1H), 7.52 (s, 2H), 7.41 (dt, J=8.6, 4.4 Hz, 1H), 7.24-7.17. (M, 2H), 4.77 (d, J=1.6 Hz, 2H), 3.96-3.87 (m, 1H), 3.76 (t, J=7.9 Hz, 2H), 3 0.58 (t, J=7.3 Hz, 2H), 3.08-3.02 (m, 2H), 3.01-2.95 (m, 2H)
HPLCMS (Method B): [m/z]: 421.1 [M+H] ^+.
2-{1-[2-(4-Fluoro-1H-1,3-benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-[(3-fluoropyridin-2-yl)methyl ]-1,3-Oxazole-5-carboxamide (Example compound No. 3)

In a similar manner to general procedure 8, 2-(azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-5-carboxamide in MeCN (10 ml). Crude intermediate with (359) (400 mg, 1.45 mmol), N-(3-fluoro-2-nitrophenyl)prop-2-enamide (G) (335 mg, 1.59 mmol) and DBU (238 μl, 1.59 mmol). The body was obtained which was partially purified by flash chromatography (eluting with a gradient of 0-20% MeOH/DCM). The intermediate was further reacted with iron powder (76 mg) in AcOH (3 ml) and the title compound (52 mg, 34%) was beige after purification by flash column chromatography (eluting with a gradient of 0-35% MeOH/DCM). Obtained as a colored solid.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.38-8.34 (m, 1H), 7.69 (s, 1H), 7.65-7.60 (m, 1H), 7 .44-7.39 (m, 1H), 7.31 (d, J=8.2 Hz, 1H), 7.21-7.15 (m, 1H), 6.98-6.92 (m, 1H), 4.77 (d, J=1.6 Hz, 2H), 3.92 (p, J=7.1 Hz, 1H), 3.77 (t, J=8.0 Hz, 2H), 3. 58 (t, J=7.4 Hz, 2H), 3.08-3.02 (m, 2H), 3.02-2.96 (m, 2H)
HPLC MS (Method G): [m/z]: 439.2 [M+H] ^+.
2-{1-[2-(5-Fluoro-1H-1,3-benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-[(3-fluoropyridin-2-yl)methyl ]-1,3-Oxazole-5-carboxamide (Example compound No. 5)

In a manner similar to general procedure 8, 2-(azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-5-carboxamide in MeCN (30 ml). Crude intermediate with (359) (581 mg, 2.1 mmol), N-(5-fluoro-2-nitrophenyl)prop-2-enamide (J) (371 mg, 1.77 mmol) and DBU (346 μl, 2.31 mmol). The product was obtained which was further reacted with iron powder (186 mg, 3.34 mmol) in AcOH (20 ml) to give the title compound (205 mg, 56%) as a white solid after purification by basic preparative HPLC. It was

1H-NMR (MeOD, 500 MHz): d[ppm]=8.37 (dt, J=4.6, 1.2 Hz, 1H), 7.69 (s, 1H), 7.62 (ddd, J=) 9.8, 8.4, 1.2 Hz, 1H), 7.51-7.45 (m, 1H), 7.41 (dt, J=8.7, 4.4 Hz, 1H), 7.22 (Dd, J=9.1, 2.1 Hz, 1H), 7.03-6.96 (m, 1H), 4.77 (d, J=1.6 Hz, 2H), 3.95-3. 86 (m, 1H), 3.76 (t, J=8.0 Hz, 2H), 3.57 (t, J=7.4 Hz, 2H), 3.06-3.01 (m, 2H), 3.00-2.94 (m, 2H)
HPLCMS (Method B): [m/z]: 439.2 [M+H] ^+.
General scheme 1 above:
General Procedure 1: Ethyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate (1)

Ethyl 3-bromo-2-oxopropanoate (12.35 ml, 107.69 mmol) and tert-butyl(3-amino-3-thioxopropyl)carbamate (20 g, 97.9 mmol) in EtOH (200 ml) suspended. To the suspension was added CaCO ₃ (5.3 g, 52.87 mmol) in small portions and the reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated in vacuo and the residue was partitioned between EtOAc (200 ml) and saturated NaHCO ₃ (100ml). The organic layer was separated, water (100 ml), washed with brine (100ml), dried (MgSO _4), filtered, and concentrated in vacuo to give the required product. Purification by flash column chromatography (isocratic elution 20% EtOAc/heptane) provided the title compound (22 g, 69.6%) as a yellow solid.

1H-NMR (Methanol-d4, 250MHz): d[ppm]=8.29(s, 1H), 4.39(q, J=7.1Hz, 2H), 3.47(t, J=6. 5Hz, 2H), 3.22 (t, J=6.5Hz, 2H), 1.41 (d, J=6.2Hz, 14H)
HPLCMS (Method A): [m/z]: 301.0 [M+H] ^+.
Methyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate (2)

In a manner similar to General Procedure 1 tert-butyl(3-amino-3-thioxopropyl)carbamate (10 g, 48.95 mmol) in EtOH (120 ml), methyl 3-bromo-2-oxopropanoate ( After purification by flash chromatography (eluting with a gradient of 20-80% EtOAc/heptane) with 5.73 ml, 53.85 mmol) and CaCO ₃ (0.9 ml, 26.43 mmol), the title compound (10.2 g, 60 %, purity 83%) was obtained as a yellow solid.

HPLCMS (Method A): [m/z]: 286.9 [M+H] ^+.
Methyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-1,3-thiazole-4-carboxylate (3)

In a manner similar to General Procedure 1, tert-butyl N-(2-carbamothioylethyl)carbamate (0.89 g, 4.35 mmol) in EtOH (15 ml), methyl 3-bromo-2-oxobutanoate. (0.93 g, 4.78 mmol) and CaCO ₃ (0.23 g, 2 mmol) by, after purification by flash column chromatography (eluting with a gradient of 10 to 60% EtOAc / heptane) to give the title compound (0.769g, 58 %) was obtained as a yellow oil.

1H-NMR (CDCl3, 250MHz): d [ppm] = 4.88 (s, 1H), 3.95 (s, 3H), 3.55 (q, J = 6.5Hz, 2H), 3.17. (T, J=6.5 Hz, 2H), 2.76 (s, 3H), 1.46 (s, 9H)
HPLCMS (Method A): [m/z]: 301.05 [M+H] ^+.
Ethyl 2-(3-{[(tert-butoxy)carbonyl]amino}propyl)-1,3-thiazole-4-carboxylate (4)

In a manner similar to General Procedure 1, tert-butyl N-(3-carbamothioylpropyl)carbamate (535 mg, 2.45 mmol) in EtOH (10 ml), ethyl 3-bromo-2-oxopropanoate (0 .31 ml, 2.7 mmol) and CaCO ₃ (132 mg, 1.32 mmol) after purification by flash column chromatography (eluting with a gradient of 0-50% EtOAc/heptane) the title compound (726 mg, 93%) is yellow. Obtained as an oil.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.38 (s, 1H), 6.90 (s, 1H), 4.29 (q, J=7.1 Hz, 2H), 3 15-2.90 (m, 4H), 1.83 (m, 2H), 1.38 (s, 9H), 1.30 (t, J=7.1Hz, 3H)
HPLCMS (Method A): [m/z]: 315 [M+H] ^+.
General Procedure 2: Methyl 2-(2-aminoethyl)-1,3-thiazole-4-carboxylate (5)

4M HCl in dioxane (44 ml, 176 mmol) was added to methyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate (2) (10.2 g, 35. 62 mmol) in dioxane and the mixture was stirred at room temperature for 12 hours and then at 40° C. for 24 hours. The mixture was cooled to room temperature and evaporated in vacuo. The residue was dissolved in DCM (20 ml), washed with saturated NaHCO _{3 (3} × 10ml). The combined aqueous phases were re-extracted with diethyl ether (3×100 ml) and the combined organic phases dried (MgSO ₄ ), filtered and evaporated in vacuo to give the title compound (1.96 g, 30%). Obtained as a brown solid.

HPLC MS (Method A): [m/z]: 186.9 [M+H] ^+.
General Procedure 3: Methyl 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-1,3-thiazol-4-carboxylate (6)

Methyl 2-(2-aminoethyl)-1,3-thiazole-4-carboxylate (5) (1.96 g, 10.52 mmol), 1H-benzimidazole-2-carbaldehyde (2.31 g, 15.79 mmol). ) And DIPEA (1.83 ml, 10.52 mmol) in MeOH (100 ml) was stirred at room temperature for 12 hours. The reaction mixture was cooled to 0° C., NaBH ₄ (0.597 g, 15.79 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, the residue was dissolved in EtOAc (100 ml) and washed with saturated Na2CO3 (2 x 50 ml). The combined aqueous layers were extracted with EtOAc (3 × 50ml), the combined organic layers were dried (MgSO _4), filtered and evaporated in vacuo. Purification by flash column chromatography (KP-NH, eluting with a gradient of 0-10% MeOH/DCM) gave the title compound (1.4 g, 38%, 90% pure) as a tan solid.

1H-NMR (Methanol-d4, 250MHz): d[ppm]=8.27 (s, 1H), 7.60-7.49 (m, 2H), 7.29-7.17 (m, 2H). , 4.09 (s, 2H), 3.92 (s, 3H), 3.26 (t, J=6.3 Hz, 2H), 3.10 (t, J=6.8 Hz, 2H)
HPLCMS (Method A): [m/z]: 317 [M+H] ^+.
General procedure 4:
tert-Butyl 2-({[(tert-butoxy)carbonyl]({2-[4-(methoxycarbonyl)-1,3-thiazol-2-yl]ethyl})amino}methyl)-1H-1,3 -Benzodiazole-1-carboxylate (7)

Methyl 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-1,3-thiazol-4-carboxylate (6) (74%, 2.94 g, 6. 88 mmol), Boc ₂ O (3.75 g, 17.19 mmol) and TEA (2.38 ml, 17.19 mmol) in THF (60 ml) was added DMAP (168 mg, 1.38 mmol) and the reaction was left at room temperature. It was stirred for 16 hours. The reaction was evaporated to dryness, diluted with EtOAc (100 ml) and washed with water (3 x 50 ml). The organics were dried over MgSO _4, filtered, and evaporated to dryness. The crude residue was purified by FCC eluting with 0-100% EtOAc in heptane to give 3.8 g of the desired product.

General Procedure 5: 2-(2-{[(tert-butoxy)carbonyl]({1-[(tert-butoxy)carbonyl]-1H-1,3-benzodiazol-2-yl}methyl)amino } Ethyl)-1,3-thiazole-4-carboxylic acid (8)

Lithium hydroxide (0.48 mg, 20.08 mmol) was added to tert-butyl 2-({[(tert-butoxy)carbonyl]({2-[4-(methoxycarbonyl)-1,3-thiazol-2-yl]. Ethyl})amino}methyl)-1H-1,3-benzodiazol-1-carboxylate (7) (3.8 g, 6.69 mmol) in THF/water (40 ml/10 ml) at 0°C. did. The reaction mixture was stirred at room temperature for 48 hours. The mixture was concentrated in vacuo and acidified with AcOH to pH ~3-4. The reaction mixture was extracted with THF/EtOAc (3:1, 3×50 ml). The combined organic extracts were washed with brine (100ml), dried (MgSO _4), filtered, reduced in vacuo and azeotroped with heptane (3 × 50 ml), the title compound (2.4 g, 84.6%) was obtained as a yellow foam.

1H-NMR (Methanol-d4, 250MHz): d[ppm]=8.15(d, J=17.0Hz, 1H), 7.69(s, 2H), 7.27(dd, J=6. 1, 3.2 Hz, 2H), 4.79 (s, 2H), 3.87-3.74 (m, 2H), 3.40-3.33 (m, 3H), 1.38-1. 01 (m, 10H)
HPLC MS (method A): [m/z]: 403 [M+H] ^+.
General Procedure 6: tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyridin-2-ylmethyl)carbamoyl]-1,3-thiazole -2-yl}ethyl)carbamate (9)

2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylic acid (8) (3 g, 7.08 mmol), 1-(pyridin-2-yl)methanamine (1.1 ml, 10.62 mmol), DIPEA (3.7 ml, 21.24 mmol) and DMF (50 ml) in a stirred solution at room temperature with HATU(5. 0.39 g, 14.16 mmol) was added. The reaction mixture was allowed to stir at room temperature for 16 hours.

The reaction was diluted with EtOAc (100 ml), washed with saturated NaHCO ₃ (3×50 ml) and brine (3×50 ml). The organic layer was separated, dried (MgSO4), filtered and evaporated to dryness. The crude residue was purified by flash column chromatography (kp-NH, eluting with a gradient of 20-100% EtOAc in heptane) then azeotroped with heptane to give the title compound (2.2g, 62%) as a yellow foam. Was obtained as.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.49 (d, J=4.4 Hz, 1H), 8.10 (s, 1H), 7.80 (td, J=7.8, 1.7 Hz, 1 H), 7.54 (s, 2 H), 7.42 (d, J=7.9 Hz, 1 H), 7.31 (dd, J=7.1, 5.2 Hz, 1 H), 7.26-7.20 (m, 2H), 4.75 (d, J=12.3Hz, 2H), 4.70 (s, 2H), 3.92-3.79 (m, 2H), 3.36 (d, J=8.1 Hz, 1H), 1.43-1.25 (m, 10H)
HPLCMS (Method D): [m/z]: 493.1 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(cyclohexylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate (10)

In a manner similar to general procedure 6 at room temperature for 1 hour 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino in DMF (4 ml). ] Ethyl}-1,3-thiazole-4-carboxylic acid (8) (99.8 mg, 0.248 mmol), cyclohexylmethanamine (33.69 mg, 0.298 mmol), DIPEA (96.16 mg, 0.744 mmol). And HATU (113.16 mg, 0.298 mmol) after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH/DCM) to afford the title compound (116 mg, 47% pure) as an off-white oil. .. The title compound was used in the next step without further purification.

HPLC MS (Method H): [m/z]: 498.7 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1,3- Thiazol-2-yl]ethyl}carbamate (11)

In a manner similar to general procedure 6 at room temperature for 1 hour 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino in DMF (4 ml). ] Ethyl}-1,3-thiazole-4-carboxylic acid (8) (99.8 mg, 0.248 mmol), 1,2,3,4-tetrahydroisoquinoline (39.64 mg, 0.298 mmol), DIPEA (96 .16 mg, 0.744 mmol) and HATU (113.16 mg, 0.298 mmol) after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH/DCM), the title compound (124 mg, 59% purity). Was obtained as an off-white oil. The title compound was used in the next step without further purification.

HPLC MS (Method H): [m/z]: 518.7 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(thiophen-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl} Ethyl) carbamate (12)

2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylic acid (8) (150 mg, To a solution of 0.373 mmol) in DMF (10 ml) was added 1H-1,2,3-benzotriazol-1-ol (50 mg, 0.373 mmol) and EDC:HCl (71 mg, 0.373 mmol) at 0°C. did. After allowing the reaction mixture to stir for 15 minutes, TEA (38 mg, 0.373 mmol) was added followed by thiophen-2-ylmethanamine (42 mg, 0.373 mmol). The reaction mixture was allowed to warm to room temperature and stir overnight. The title compound (185 mg, 16% purity) was obtained after work up according to general procedure 6. It was used in the next step without purification.

HPLC MS (Method H): [m/z]: 498.6 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[benzyl(methyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate (13)

In a manner similar to general procedure 6 at room temperature for 1 hour 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino in DMF (4 ml). ] Ethyl}-1,3-thiazole-4-carboxylic acid (8) (99.8 mg, 0.248 mmol), benzyl(methyl)amine (36.06 mg, 0.298 mmol), DIPEA (96.16 mg, 0. 744 mmol) and HATU (113.16 mg, 0.298 mmol) after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH/DCM) to afford the title compound (118 mg, 55% pure) as an off-white oil. Was given. The title compound was used in the next step without further purification.

HPLC MS (Method H): [m/z]: 506.7 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-(morpholine-4-carbonyl)-1,3-thiazol-2-yl]ethyl}carbamate (14)

In a manner similar to general procedure 6 at room temperature for 1 hour 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino in DMF (4 ml). ] Ethyl}-1,3-thiazole-4-carboxylic acid (8) (99.8 mg, 0.248 mmol), morpholine (25.93 mg, 0.298 mmol), DIPEA (96.16 mg, 0.744 mmol) and HATU. After purification by (113.16 mg, 0.298 mmol) by flash column chromatography (eluting with a gradient of 0-10% MeOH/DCM), the title compound (110 mg) was obtained as an off-white oil. The title compound was used in the next step without further purification.

tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[methyl(phenyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate (15)

In a manner similar to general procedure 6 at room temperature for 1 hour 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino in DMF (4 ml). ] Ethyl}-1,3-thiazole-4-carboxylic acid (8) (99.8 mg, 0.248 mmol), N-methylaniline (31.89 mg, 0.298 mmol), DIPEA (96.16 mg, 0.744 mmol) ) And HATU (113.16 mg, 0.298 mmol) after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH/DCM) to give the title compound (118 mg, 59% pure) as an off-white oil. It was The title compound was used in the next step without further purification.

HPLC MS (Method H): [m/z]: 492.7 [M+H] ^+.
tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(pyrrolidin-1-yl)phenyl]methyl}carbamoyl)-1, 3-Thiazol-2-yl]ethyl}carbamate (16)

In a similar manner to General Procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino in DMF (5 ml) for 1 hour at room temperature. ] Ethyl}-1,3-thiazole-4-carboxylic acid (8) (200 mg, 0.497 mmol), [3-(pyrrolidin-1-yl)phenyl]methanamine (105 mg, 0.596 mmol), DIPEA (193 mg, 1.491 mmol) and HATU (227 mg, 0.596 mmol) and after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH/DCM), the title compound (100 mg, 30%, 84% purity) is off-white. Obtained as an oil.

HPLC MS (Method H): [m/z]: 561.7 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-(dimethylcarbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate (17)

In a similar manner to General Procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino in DMF (10 ml) for 1 hour at room temperature. ] Ethyl}-1,3-thiazole-4-carboxylic acid (8) (100 mg, 0.248 mmol), dimethylamine (2M solution in THF) (13 mg, 0.298 mmol), DIPEA (96 mg, 0.745 mmol) and After purification by HATU (113 mg, 0.298 mmol) by flash column chromatography (eluting with a gradient of 0-10% MeOH/DCM), the title compound (90 mg, 67%, 80% purity) was obtained as a white solid. ..

HPLC MS (Method H): [m/z]: 430.6 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[cyclohexyl(propan-2-yl)carbamoyl]-1,3-thiazol-2-yl } Ethyl) carbamate (18)

In a manner similar to general procedure 6 at room temperature for 1 hour 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino in DMF (4 ml). ] Ethyl}-1,3-thiazole-4-carboxylic acid (8) (99.8 mg, 0.248 mmol), N-(propan-2-yl)cyclohexanamine (42.04 mg, 0.298 mmol), DIPEA( After purification by flash column chromatography (eluting with a gradient of 0-10% MeOH/DCM) by 96.16 mg, 0.744 mmol) and HATU (113.16 mg, 0.298 mmol) the title compound (124 mg, 17% pure). ) Was obtained as an off-white oil. The title compound was used in the next step without further purification.

HPLC MS (Method H): [m/z]: 526.8 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(2-phenylpropan-2-yl)carbamoyl]-1,3-thiazole-2 -Yl}ethyl)carbamate (19)

In a manner similar to general procedure 6 at room temperature for 1 hour 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino in DMF (4 ml). ] Ethyl}-1,3-thiazole-4-carboxylic acid (8) (99.8 mg, 0.248 mmol), 2-phenylpropan-2-amine (40.24 mg, 0.298 mmol), DIPEA (96.16 mg). , 0.744 mmol) and HATU (113.16 mg, 0.298 mmol) after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH/DCM), the title compound (120 mg, purity 51%) is off-white. Obtained as an oil. The title compound was used in the next step without further purification.

HPLC MS (method H): [m/z]: 520.7 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-(benzylcarbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate (20)

In a manner similar to General Procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (10 ml). , 3-thiazole-4-carboxylic acid (8) (350 mg, 0.87 mmol), phenylmethanamine (103 mg, 0.957 mmol), DIPEA (337 mg, 2.61 mmol) and HATU (397 mg, 1.04 mmol). After purification by flash column chromatography (eluting with a gradient of 0-10% MeOH/DCM), the title compound (390 mg, 89% pure) was obtained as a white solid.

HPLC MS (Method H): [m/z]: 492.6 [M+H] ^+.
tert-Butyl N-{2-[4-(benzylcarbamoyl)-1,3-thiazol-2-yl]ethyl}-N-[(1-methyl-1H-1,3-benzodiazol-2-yl ) Methyl] carbamate (21)

tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-(benzylcarbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate (20) To a stirred solution of (380 mg, 0.773 mmol) and TEA (78 mg, 0.773 mmol) in DCM (15 ml) was added MeI (165 mg, 1.159 mmol) under argon atmosphere. The reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness under vacuum to give the title compound (280 mg, 72% pure) as an off-white solid. The crude product was used in the next step without purification.

HPLC MS (method H): [m/z]: 506.6 [M+H] ^+.
tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyridin-3-ylmethyl)carbamoyl]-1,3-thiazol-2-yl} Ethyl) carbamate (22)

In a similar manner to General Procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (8 ml). , 3-Thiazol-4-carboxylic acid (8) (199.6 mg, 0.496 mmol), pyridin-3-ylmethanamine (59 mg, 0.546 mmol), DIPEA (192.3 mg, 1.488 mmol) and HATU ( After purification by flash column chromatography (eluting with a gradient of 0-10% MeOH/DCM) by 226 mg, 0.595 mmol) the title compound (184 mg, 75%) was obtained as a white solid.

_{1H-NMR (CDCl 3, 400MHz} ): d [ppm] = 8.61 (d, J = 1.6Hz, 1H), 8.52 (d, J = 3.6Hz, 1H), 7.96 (s , 1H), 7.81 (s, 1H), 7.73-7.67 (m, 1H), 7.55 (dd, J=6.0, 3.2 Hz, 2H), 7.28 (s. , 1H), 7.25 (dd, J=6.1, 3.2 Hz, 2H), 4.63 (d, J=6.6 Hz, 4H), 3.77 (t, J=6.5 Hz, 2H), 3.22 (t, J=6.3Hz, 2H), 1.37 (s, 9H)
HPLC MS (method H): [m/z]: 493.4 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyridin-4-ylmethyl)carbamoyl]-1,3-thiazol-2-yl} Ethyl) carbamate (23)

In a similar manner to General Procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (8 ml). , 3-Thiazol-4-carboxylic acid (8) (199.6 mg, 0.496 mmol), pyridin-4-ylmethanamine (59 mg, 0.546 mmol), DIPEA (192.3 mg, 1.488 mmol) and HATU ( 226 mg, 0.595 mmol) afforded the title compound (140 mg, 57%) as a white solid after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH/DCM).

1H-NMR (CDCl ₃ , 400 MHz): d[ppm]=8.56 (d, J=5.9 Hz, 2H), 7.98 (s, 1H), 7.82 (s, 1H), 7. 59-7.48 (m, 2H), 7.24 (dd, J=6.0, 3.2 Hz, 4H), 4.62 (d, J=6.6 Hz, 4H), 3.78 (t , J=6.5 Hz, 2H), 3.25 (t, J=6.4 Hz, 2H), 1.41 (d, J=13.9 Hz, 9H)
HPLC MS (method H): [m/z]: 493.4 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[3-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)- 1,3-thiazol-2-yl]ethyl}carbamate (24)

In a similar manner to General Procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl in DMF (2.5 ml). -1,3-Thiazol-4-carboxylic acid (8) (80.09 mg, 0.199 mmol), [3-(trifluoromethyl)pyridin-2-yl]methanamine hydrochloride (46.54 mg, 0.219 mmol) , DIPEA (102.9 mg, 0.796 mmol) and HATU (90.8 mg, 0.239 mmol) after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH/DCM), the title compound (85 mg, 76%, purity 98%) was obtained as a white solid.

HPLC MS (Method H): [m/z]: 561.5 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl]-1 ,3-thiazol-2-yl}ethyl)carbamate (25)

In a similar manner to General Procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl in DMF (2.5 ml). -1,3-Thiazol-4-carboxylic acid (8) (80.09 mg, 0.199 mmol), N-methyl-5,6,7,8-tetrahydroquinolin-8-amine dihydrochloride (48.4 mg, 0.219 mmol), DIPEA (102.9 mg, 0.796 mmol) and HATU (90.8 mg, 0.239 mmol) after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH/DCM). The compound (92 mg, 87%) was obtained as a white solid.

HPLC MS (Method H): [m/z]: 533.5 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({5H,6H,7H-cyclopenta[b]pyridin-7-yl}carbamoyl)- 1,3-thiazol-2-yl]ethyl}carbamate (26)

In a similar manner to General Procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl in DMF (2.5 ml). -1,3-thiazole-4-carboxylic acid (8) (80.9 mg, 0.199 mmol), N-methyl-5H,6H,7H-cyclopenta[b]pyridin-7-amine hydrochloride (37.35 mg, 0.219 mmol), DIPEA (102.9 mg, 0.796 mmol) and HATU (90.8 mg, 0.239 mmol) after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH/DCM). The compound (90 mg, 87%) was obtained as a white solid.

HPLC MS (Method H): [m/z]: 519.5 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(4-methylmorpholin-2-yl)methyl]carbamoyl}-1,3- Thiazol-2-yl)ethyl]carbamate (27)

In a similar manner to General Procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (60 ml). , 3-thiazole-4-carboxylic acid (8) (3 g, 7.545 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (2.26 g, 11.18 mmol), DIPEA (12 .98 ml, 74.54 mmol) and HATU (4.251 g, 11.18 mmol), eluting with flash column chromatography (kp-NH, 20-100% EtOAc/heptane, followed by a gradient of 0-20% MeOH/EtOAc). After purification by (), the title compound (4.13 mg, 89%) was obtained as a yellow oil.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.29 (s, 1H), 8.69 (s, 1H), 8.36 (s, 1H), 8.17 (s, 1H). ), 7.70(t, J=9.5Hz, 1H), 7.48(s, 2H), 7.40(dt, J=8.6, 4.4Hz, 1H), 7.14(s). , 2H), 4.66 (d, J=8.8 Hz, 4H), 3.73 (s, 2H), 2.52 (s, 2H), 1.99 (s, 4H), 1.26 ( d, J=44.9 Hz, 9H)
HPLCMS (Method A): [m/z]: 511.15 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(4-methylmorpholin-2-yl)methyl]carbamoyl}-1,3- Thiazol-2-yl)ethyl]carbamate (28)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (4 ml). , 3-thiazol-4-carboxylic acid (8) (99.8 mg, 0.248 mmol), (4-methylmorpholin-3-yl)methanamine (35.5 mg, 0.273 mmol), DIPEA (96.16 mg, 0). .744 mmol) and T3P (189.4 mg, 0.298 mmol) after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH/DCM) to give the title compound (90 mg, 70%) as a white solid. Was given.

1H-NMR (CDCl ₃ , 400 MHz): d [ppm] = 7.90 (s, 1H), 7.59 (s, 3H), 7.28 (t, J = 3.6 Hz, 1H), 4. 64 (s, 2H), 3.79 (td, J = 12.0, 4.7Hz, 5H), 3.70-3.59 (m, 2H), 3.47 (ddd, J = 14.7). , 10.3, 6.6 Hz, 4H), 3.22 (t, J = 6.4 Hz, 2H), 2.74 (d, J = 11.4 Hz, 1H), 2.49-2.32 ( m, 6H), 1.40 (s, 9H)
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6-methylpyridin-2-yl)methyl]carbamoyl}-1,3- Thiazol-2-yl)ethyl]carbamate (29)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (4 ml). , 3-thiazole-4-carboxylic acid 6 (99.8 mg, 0.248 mmol), (6-methylpyridin-2-yl)methanamine (33.33 mg, 0.273 mmol), DIPEA (96.16 mg, 0.744 mmol). ) And T3P (189.4 mg, 0.298 mmol) after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH/DCM) to give the title compound (95 mg, 75%) as a white solid. ..

1H-NMR (CDCl ₃ , 400 MHz): d[ppm]=8.14 (s, 1H), 7.90 (s, 1H), 7.55 (dd, J=14.1, 6.6 Hz, 3H) ), 7.23 (dd, J=6.0, 3.2 Hz, 2H), 7.14 (d, J=7.7 Hz, 1H), 7.06 (d, J=7.7 Hz, 1H) , 4.71 (d, J=5.5 Hz, 2H), 4.66 (s, 2H), 3.80 (t, J=6.3 Hz, 2H), 3.22 (t, J=6. 4Hz, 2H), 2.55 (s, 3H), 1.34 (s, 9H)
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(5-fluoropyridin-2-yl)methyl]carbamoyl}-1,3- Thiazol-2-yl)ethyl]carbamate (30)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (4 ml). , 3-thiazole-4-carboxylic acid (8) (99.8 mg, 0.248 mmol), (5-fluoropyridin-2-yl)methanamine (34.41 mg, 0.273 mmol), DIPEA (96.16 mg, 0). 0.744 mmol) and T3P (189.4 mg, 0.298 mmol) after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH/DCM) to give the title compound (89 mg, 70%) as a white solid. Was given.

1H-NMR (CDCl ₃ , 400 MHz): d[ppm]=8.44 (s, 1H), 8.12 (s, 1H), 7.92 (s, 1H), 7.56 (s, 2H). , 7.44-7.30 (m, 2H), 7.25 (dd, J = 6.1, 3.2Hz, 2H), 4.73 (d, J = 5.6Hz, 2H), 4. 66 (s, 2H), 3.79 (t, J = 6.3Hz, 2H), 3.23 (t, J = 6.3Hz, 2H), 3.04 (s, 1H), 1.34 ( s, 9H)
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyrimidin-4-ylmethyl)carbamoyl]-1,3-thiazol-2-yl} Ethyl) carbamate (31)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino in DMF (2 ml) overnight at room temperature. ] Ethyl}-1,3-thiazole-4-carboxylic acid (8) (150 mg, 0.373 mmo), pyrimidin-4-ylmethanamine (48.8 mg, 0.447 mmol), DIPEA (48.1 mg, 0. 373 mmol) and HATU (141.7 mg, 0.373 mmol) afforded the title compound (80 mg, 60% pure) after purification by flash column chromatography (eluting with a gradient of 10% MeOH in DCM). ..

HPLC MS (Method H): [m/z]: 494.6 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(5-methoxypyridin-2-yl)methyl]carbamoyl}-1,3- Thiazol-2-yl)ethyl]carbamate (32)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino in DMF (2 ml) overnight at room temperature. ] Ethyl}-1,3-thiazole-4-carboxylic acid (8) (150 mg, 0.373 mmo), (5-methoxypyridin-2-yl)methanamine (48.17 mg, 0.447 mmol), DIPEA (48. 1 mg, 0.373 mmol) and HATU (141.7 mg, 0.373 mmol) after purification by flash column chromatography (eluting with a gradient of 10% MeOH in DCM) the title compound (80 mg, 41%) as a brown solid. Was obtained.

HPLC MS (Method H): [m/z]: 523.6 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyrazin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl} Ethyl) carbamate (33)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino in DMF (2 ml) overnight at room temperature. ] Ethyl}-1,3-thiazole-4-carboxylic acid (8) (150 mg, 0.373 mmol), pyrazin-2-ylmethanamine (48.8 mg, 0.447 mmol), DIPEA (192.68 mg, 1. After purification by flash column chromatography (eluting with a gradient of 10% MeOH in DCM) with 491 mmol) and HATU (141.7 mg, 0.373 mmol), the title compound (95 mg, 52%) was obtained as a yellow solid.

HPLC MS (Method H): [m/z]: 394.5 [M+H-Boc] ^+.
tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6-oxo-1,6-dihydropyridin-2-yl)methyl]carbamoyl} -1,3-Thiazol-2-yl)ethyl]carbamate (34)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino in DMF (2 ml) overnight at room temperature. ] Ethyl}-1,3-thiazole-4-carboxylic acid (8) (150 mg, 0.373 mmol), 6-(aminomethyl)-1,2-dihydropyridin-2-one (55.52 mg, 0.447 mmol) , DIPEA (48.17 mg, 0.373 mmol) and HATU (141.7 mg, 0.373 mmol) after purification by flash column chromatography (eluting with a gradient of 10% MeOH in DCM) (90 mg, 47%). ) Was obtained as a yellow solid.

HPLC MS (Method H): [m/z]: 509.6 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6-carbamoylpyridin-3-yl)methyl]carbamoyl}-1,3- Thiazol-2-yl)ethyl]carbamate (35) and tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6-cyanopyridine- 3-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (36)

In a similar manner to General Procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino in DMF (1 ml) at room temperature for 18 hours. ] Ethyl}-1,3-thiazole-4-carboxylic acid (8) (100 mg, 0.248 mmol), 5-(aminomethyl)pyridine-2-carbonitrile (33 mg, 0.248 mmol), HATU (189 mg, 0). .497 mmol) and DIPEA (96 mg, 0.745 mmol) after purification by flash column chromatography (DCM:MeOH, 9:1) to give a 2:1 ratio of boc amine and boc nitrile (80 mg). This mixture was used in the next step without separation.

HPLCMS (Method H): [m/z]: 418.5 [M+H-boc] ⁺ and 436.3 [M+H-boc] ^+.
tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3,5-dimethylpyridin-2-yl)methyl]carbamoyl}-1, 3-Thiazol-2-yl)ethyl]carbamate (37)

In a manner similar to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino in DMF (6 ml) for 4 hours at room temperature. ] Ethyl}-1,3-thiazole-4-carboxylic acid (8) (0.3 g, 0.708 mmol), (3,5-dimethylpyridin-2-yl)methanamine hydrochloride (0.183 g, 1.062 mmol) ), DIPEA (0.555 ml, 3.187 mmol) and HATU (0.404 g, 1.062 mmol) by flash column chromatography (kp-NH, EtOAc (30%)/heptane (70%) followed by 100%. After purification by elution with a gradient of EtOAc) the title compound (0.198 g, 51%) was obtained as a yellow oil.

1H-NMR (DMSO-d6,500MHz): d [ppm] = 12.29 (s, 1H), 8.75 (s, 1H), 8.19 (s, 2H), 7.56 (d, J). =7.6 Hz, 1H), 7.48-7.40 (m, 2H), 7.14 (p, J=7.0Hz, 2H), 4.66 (s, 2H), 4.53 (d). , J=4.8 Hz, 2H), 3.73 (s, 2H), 2.27 (s, 3H), 2.23 (s, 3H), 1.31 (s, 9H).
HPLCMS (Method A): [m/z]: 521.15 [M+H] ^+.
tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyrimidin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl} Ethyl) carbamate (38)

In a similar manner to General Procedure 6 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DCM (5 ml). ,3-Thiazol-4-carboxylic acid (8) (100 mg, 0.20 mmol), 1-(pyrimidin-2-yl)methanamine (22 mg, 0.20 mmol), DIPEA (0.1 ml, 0.60 mmol) and HATU. After purification by (113 mg, 0.30 mmol) by flash column chromatography (eluting with a gradient of 0-20% MeOH/EtOAc), the title compound (86 mg, 73%) was obtained as a brown residue.

HPLC MS (Method A): [m/z]: 494.1 [M+H] ^+.
tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(4-methylpiperazin-1-yl)phenyl]methyl}carbamoyl) -1,3-Thiazol-2-yl]ethyl}carbamate (39)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (2 ml). , 3-thiazole-4-carboxylic acid (8) (130 mg, 0.24 mmol, purity 75%), 1-[2-(4-methylpiperazin-1-yl)phenyl]methanamine (75 mg, 0.36 mmol), After purification by basic preparative HPLC with DIPEA (127 μl, 0.73 mmol) and HATU (138 mg, 0.36 mmol), the title compound (13 mg, 9%) was obtained as a white solid.

HPLCMS (Method D): [m/z]: 590.3 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(2,6-difluorophenyl)methyl]carbamoyl}-1,3-thiazole- 2-yl)ethyl]carbamate (40)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (2 ml). , 3-thiazole-4-carboxylic acid (8) (110 mg, 0.25 mmol, purity 90%), 1-(2,6-difluorophenyl)methanamine (53 mg, 0.37 mmol), DIPEA (0.13 ml, 0). 0.74 mmol) and HATU (140 mg, 0.37 mmol) after purification by flash column chromatography (kp-NH, eluting with a gradient of 2-100% EtOAc/heptane) to give the title compound (90 mg, 68%) as a yellow oil. Was obtained as.

HPLC MS (Method E): [m/z]: 528.3 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(dimethylamino)phenyl]methyl}carbamoyl)-1,3-thiazole -2-yl]ethyl} carbamate (41)

2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino] in DMF (2 ml) at 50° C. in a similar manner to general procedure 6. Ethyl}-1,3-thiazole-4-carboxylic acid (8) (109 mg, 0.22 mmol, purity 80%), 2-(aminomethyl)-N,N-dimethylaniline (66 mg, 0.44 mmol), DIPEA. After purification by flash column chromatography (kp-NH, eluting with a gradient of 5-100% EtOAc/heptane) with (226 μl, 1.30 mmol) and HATU (240 mg, 0.64 mmol), the title compound (73 mg, 61%). ) Was obtained as an orange oil.

HPLC MS (Method D): [m/z]: 535.2 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(2-cyanophenyl)methyl]carbamoyl}-1,3-thiazole-2- (Il) ethyl] carbamate (42)

2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino] in DMF (2 ml) at 50° C. in a similar manner to general procedure 6. Ethyl}-1,3-thiazole-4-carboxylic acid (8) (109 mg, 0.22 mmol, purity 80%), 2-(aminomethyl)benzonitrile hydrochloride (74 mg, 0.44 mmol), DIPEA (226 μl, After purification by flash column chromatography (kp-NH, elution with a gradient of 5-100% EtOAc/heptane) with 1.30 mmol) and HATU (240 mg, 0.64 mmol), the title compound (54 mg, 30%, purity 63). %) was obtained as an orange oil.

HPLC MS (Method D): [m/z]: 517.2 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(trifluoromethoxy)phenyl]methyl}carbamoyl)-1,3- Thiazol-2-yl]ethyl}carbamate (43)

In a manner similar to general procedure 6 at 50° C., 2 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino in DMF (2 ml). ] Ethyl}-1,3-thiazole-4-carboxylic acid (8) (109 mg, 0.22 mmol, purity 80%), 1-[2-(trifluoromethoxy)phenyl]methanamine (103 mg, 0.54 mmol), After purification by DIPEA (283 μl, 1.63 mmol) and HATU (248 mg, 0.65 mmol) by flash column chromatography (kp-NH, eluting with a gradient of 8-100% EtOAc/heptane), the title compound (110 mg, 78 %, 88% purity) was obtained as a yellow oil.

HPLC MS (Method E): [m/z]: 576.2 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(1-phenylethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl ) Carbamate (44)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (2 ml). , 3-thiazole-4-carboxylic acid (8) (0.11 g, 0.22 mmol, purity 80%), 1-phenylethanamine (0.07 ml, 0.54 mmol), DIPEA (0.303 ml, 1.63 mmol) ) And HATU (0.25 g, 0.64 mmol) after purification by flash column chromatography (KP-NH, eluting with a gradient of 8-100% EtOAc/heptane), the title compound (110 mg, 77%, 77% pure). ) Was obtained as a yellow oil.

HPLC MS (Method E): [m/z]: 506.2 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(difluoromethoxy)phenyl]methyl}carbamoyl)-1,3-thiazole -2-yl]ethyl}carbamate (45)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (2 ml). , 3-thiazole-4-carboxylic acid (8) (109 mg, 0.22 mmol, purity 80%), 1-[2-(difluoromethoxy)phenyl]methanamine (83 mg, 0.48 mmol), DIPEA (0.23 ml, 1.3 mmol) and HATU (250 mg, 0.65 mmol) gave the crude title compound (470 mg) as an orange oil which was used in the next step without purification.

HPLC MS (Method A): [m/z]: 558.25 [M+H] ^+.
tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(morpholine-4-sulfonyl)phenyl]methyl}carbamoyl)-1, 3-Thiazol-2-yl]ethyl}carbamate (46)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (2 ml). , 3-Thiazol-4-carboxylic acid (8) (109 mg, 0.217 mmol, purity 80%), 1-[2-(morpholin-4-ylsulfonyl)phenyl]methanamine hydrochloride (140 mg, 0.48 mmol), DIPEA (0.23 ml, 1.3 mmol) and HATU (247 mg, 0.65 mmol) gave the crude title compound (440 mg) as an orange oil after direct evaporation of the reaction mixture in vacuo. This material was used without purification.

HPLCMS (Method A): [m/z]: 641.35 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[2-(pyridin-2-yl)ethyl]carbamoyl}-1,3-thiazole -2-yl)ethyl]carbamate (47)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (2 ml). , 3-thiazole-4-carboxylic acid (8) (100 mg, 0.2 mmol, purity 80%), 2-(pyridin-2-yl)ethanamine (49 mg, 0.4 mmol), DIPEA (104 μl, 0.6 mmol). And HATU (151 mg, 0.4 mmol) after purification by flash column chromatography KP-NH eluting with a gradient of 5-100% EtOAc/heptane gave the title compound (52 mg, 52%) as a cream solid. ..

HPLC MS (Method A): [m/z]: 507.15 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(3-fluoropyridin-2-yl)carbamoyl]-1,3-thiazole-2 -Yl}ethyl)carbamate (48)

In a manner similar to General Procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole- 4-carboxylic acid (8) (80%, 150 mg, 0.3 mmol), 3-fluoropyridin-2-amine (100 mg, 0.89 mmol), DIPEA (312 μl, 1.78 mmol) and HATU (340 mg, 0.87 mmol). A solution of) in DMF (2 ml) was heated at 100° C. for 16 hours. The reaction mixture was concentrated in vacuo to give the crude title compound (705 mg) as a brown oil, which was used in the next step without purification.

HPLCMS (Method A): [m/z]: 497.10 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(2-phenylethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl ) Carbamate (49)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (2 ml). ,3-thiazole-4-carboxylic acid (8) (0.1 g, 0.25 mmol), 2-phenylethanamine (0.03 ml, 0.25 mmol), DIPEA (0.13 ml, 0.75 mmol) and HATU( After purification by flash column chromatography (eluting with a gradient of 2-100% EtOAc/heptane) by 0.14 g, 0.37 mmol), the title compound (71 mg, 56%) was obtained as a yellow oil.

HPLCMS (Method A): [m/z]: 506.2 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-fluoro-6-methylpyridin-2-yl)methyl]carbamoyl}- 1,3-thiazol-2-yl)ethyl]carbamate (50)

In a similar manner to General Procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (3 ml). , 3-Thiazol-4-carboxylic acid (8) (150 mg, 0.298 mmol, purity 80%), (3-Fluoro-6-methylpyridin-2-yl)methanamine hydrochloride (79 mg, 0.447 mmol), DIPEA. (156 μl, 0.894 mmol) and HATU (230 mg, 0.596 mmol) after purification by flash column chromatography (kp-NH, eluting with a gradient of 0-100% EtOAc/heptane), the title compound (76 mg, 48%). ) Was obtained as a pale yellow oil.

HPLC MS (Method A): [m/z]: 525.40 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[1-(pyridin-2-yl)ethyl]carbamoyl}-1,3-thiazole -2-yl)ethyl]carbamate (51)

In a similar manner to General Procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (3 ml). ,3-thiazole-4-carboxylic acid (8) (150 mg, 0.298 mmol, purity 80%), 1-(pyridin-2-yl)ethanamine (55 mg, 0.447 mmol), DIPEA (156 μl, 0.894 mmol). And HATU (227 mg, 0.596 mmol) after purification by flash column chromatography (kp-NH, eluting with a gradient of 0-100% EtOAc/heptane) to give the title compound (78 mg, 50%) as a colorless oil. It was

HPLCMS (Method A): [m/z]: 507.20 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[6-(trifluoromethyl)pyridin-3-yl]methyl}carbamoyl)- 1,3-Thiazol-2-yl]ethyl}carbamate (52)

In a similar manner to General Procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (3 ml). , 3-Thiazol-4-carboxylic acid (8) (150 mg, 0.298 mmol, purity 80%), 1-[6-(trifluoromethyl)pyridin-3-yl]methanamine (79 mg, 0.447 mmol), DIPEA. (156 μl, 0.894 mmol) and HATU (227 mg, 0.596 mmol) after purification by flash column chromatography (kp-NH, eluting with 0-100% EtOAc/heptane gradient), the title compound (92 mg, 46%). ) Was obtained as a colorless oil.

HPLCMS (Method A): [m/z]: 561.35 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-chloropyridin-2-yl)methyl]carbamoyl}-1,3- Thiazol-2-yl)ethyl]carbamate (53)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (2 ml). , 3-thiazole-4-carboxylic acid (8) (150 mg, 0.34 mmol, purity 92%), 1-(3-chloropyridin-2-yl)methanamine dihydrochloride (111 mg, 0.51 mmol), DIPEA( After purification by flash column chromatography (eluting with a gradient of kp-NH, 20-100% EtOAc/heptane) by 299 μl, 1.71 mmol) and HATU (196 mg, 0.51 mmol), the title compound (161 mg, purity 73%). , 63%) was obtained as a yellow oil.

1H-NMR (CDCl ₃ , 500 MHz): d [ppm] = 10.47 (s, 1H), 8.59 (s, 1H), 8.52-8.42 (m, 1H), 7.92 ( s, 1H), 7.71 (d, J=8.2 Hz, 2H), 7.32 (s, 1H), 7.25-7.16 (m, 3H), 4.85 (d, J= 4.8 Hz, 2H), 4.69 (s, 2H), 3.81 (s, 2H), 3.23 (t, J=6.5 Hz, 2H), 1.35 (s, 9H).
HPLCMS (Method A): [m/z]: 527.35 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(tert-butoxy)pyridin-3-yl]methyl}carbamoyl)- 1,3-Thiazol-2-yl]ethyl}carbamate (54)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (2 ml). ,3-Thiazol-4-carboxylic acid (8) (150 mg, 0.34 mmol, purity 92%), 1-(2-tert-butoxypyridin-3-yl)methanamine (93 mg, 0.514 mmol), DIPEA (179 μl). , 1.03 mmol) and HATU (196 mg, 0.51 mmol) after purification by flash column chromatography (kp-NH, eluting with a gradient of 20-100% EtOAc/heptane), the title compound (205 mg, 61%, purity). 58%) was obtained as a yellow oil.

_{1H-NMR (CDCl 3, 500MHz} ): d [ppm] = 10.09 (s, 1H), 7.89 (d, J = 15.7Hz, 2H), 7.71 (s, 1H), 7. 54-7.45 (m, 2H), 7.40 (d, J = 4.9Hz, 1H), 7.24 (s, 1H), 6.77 (td, J = 7.3, 5.0Hz). , 2H), 4.60 (s, 2H), 4.49 (d, J=6.5 Hz, 2H), 3.77 (t, J=6.5 Hz, 2H), 3.22 (s, 2H). ), 1.63 (s, 9H), 1.33 (s, 9H)
HPLC MS (method A): [m/z]: 565.15 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(1-methyl-1H-imidazol-5-yl)methyl]carbamoyl}-1 ,3-Thiazol-2-yl)ethyl]carbamate (55)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (2 ml). ,3-Thiazol-4-carboxylic acid (8) (150 mg, 0.37 mmol), (1-methyl-1H-imidazol-5-yl)methanamine (62 mg, 0.56 mmol), DIPEA (185 μl, 1.12 mmol). And HATU (213 mg, 0.56 mmol) after purification by flash column chromatography (eluting with a gradient of 0-3% MeOH/DCM) to afford the title compound (175 mg, 95%) as a yellow oil.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.08 (s, 1H), 7.58-7.52 (m, 3H), 7.26-7.20 (m, 2H). , 6.96 (s, 1H), 4.69 (d, J=12.4 Hz, 2H), 4.60 (s, 2H), 3.95-3.75 (m, 2H), 3.70. (S, 3H), 3.39-3.24 (m, 2H), 1.44-1.26 (m, 9H)
HPLC MS (Method A): [m/z]: 496.05 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(1,3-oxazol-2-ylmethyl)carbamoyl]-1,3-thiazole- 2-yl}ethyl)carbamate (56)

In a similar manner to General Procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (3 ml). , 3-Thiazol-4-carboxylic acid (8) (150 mg, 0.298 mmol, purity 80%), 1,3-oxazol-2-ylmethanamine dihydrochloride (102 mg, 0.596 mmol), DIPEA (312 μl, After purification by flash column chromatography (kp-NH, eluting with a gradient of 0-100% EtOAc/heptane) with 1.79 mmol) and HATU (227 mg, 0.596 mmol), the title compound (94 mg, 63%) was yellow. Obtained as a brown oil.

HPLCMS (Method A): [m/z]: 483.05 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(1-methyl-1H-pyrazol-3-yl)methyl]carbamoyl}-1 ,3-Thiazol-2-yl)ethyl]carbamate (57)

In a similar manner to General Procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (3 ml). , 3-Thiazol-4-carboxylic acid (8) (150 mg, 0.298 mmol, purity 80%), 1-(1-methyl-1H-pyrazol-3-yl)methanamine (50 mg, 0.45 mmol), DIPEA( After purification by flash column chromatography (kp-NH, eluting with a gradient of 0-100% EtOAc/heptane) by 156 μl, 0.894 mmol) and HATU (227 mg, 0.596 mmol) the title compound (53 mg, 34%). Was obtained as a tan oil.

HPLCMS (Method A): [m/z]: 496.45 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyridazin-3-ylmethyl)carbamoyl]-1,3-thiazol-2-yl} Ethyl) carbamate (58)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (2 ml). , 3-Thiazol-4-carboxylic acid (8) (100 mg, 0.23 mmol, purity 92%), 1-(pyridazin-3-yl)methanamine (37 mg, 0.34 mmol), DIPEA (119 μl, 0.69 mmol). And HATU (130 mg, 0.34 mmol) by flash column chromatography (kp-NH, eluting with 50-100% EtOAc/Heptane followed by a gradient of 0-15% MeOH/EtOAc) to give the title compound (101 mg , 88%) as a pale yellow oil.

HPLC MS (Method A): [m/z]: 494.1 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(1-methyl-1H-pyrazol-5-yl)methyl]carbamoyl}-1 ,3-Thiazol-2-yl)ethyl]carbamate (59)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (2 ml). , 3-thiazol-4-carboxylic acid (8) (100 mg, 0.23 mmol, purity 92%), 1-(1-methyl-1H-pyrazol-5-yl)methanamine (38 mg, 0.34 mmol), DIPEA( 119 μl, 0.69 mmol) and HATU (130 mg, 0.34 mmol) and purification by flash column chromatography (kp-NH, elution with 50-100% EtOAc/heptane, followed by 0-20% MeOH/EtOAc gradient). Afterwards, the title compound (51 mg, 45%) was obtained as a pale yellow oil.

HPLC MS (Method A): [m/z]: 496.3 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-fluoropyridin-4-yl)methyl]carbamoyl}-1,3- Thiazol-2-yl)ethyl]carbamate (60)

In a similar manner to General Procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (3 ml). , 3-Thiazol-4-carboxylic acid (8) (100 mg, 0.23 mmol, purity 92%), 1-(3-fluoropyridin-4-yl)methanamine (43 mg, 0.34 mmol), DIPEA (119 μl, 0). .69 mmol) and HATU (130 mg, 0.34 mmol) and after purification by flash column chromatography (kp-NH, eluting with a gradient of 50-100% EtOAc/heptane), the title compound (137 mg, 83%, 71% purity). ) Was obtained as a yellow oil.

_{1H-NMR (CDCl 3, 500MHz} ): d [ppm] = 10.10 (s, 1H), 8.43 (d, J = 6.0Hz, 1H), 8.37 (dd, J = 9.8 , 4.9 Hz, 2H), 7.96 (s, 1H), 7.81-7.68 (m, 2H), 7.40 (d, J=8.6 Hz, 1H), 7.35-7. .27 (m, 1H), 7.25-7.22 (m, 1H), 4.68 (d, J=6.0 Hz, 2H), 4.62 (s, 2H), 3.78 (t , J=6.5 Hz, 2H), 3.27-3.23 (m, 2H), 1.37 (s, 9H).
HPLCMS (Method A): [m/z]: 511.15 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-methylpyridin-4-yl)methyl]carbamoyl}-1,3- Thiazol-2-yl)ethyl]carbamate (61)

In a manner similar to General Procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (10 ml). , 3-thiazole-4-carboxylic acid (8) (700 mg, 1.65 mmol, purity 95%), (3-methylpyridin-4-yl)methanamine dihydrochloride (387 mg, 1.98 mmol), DIPEA (863 μl, 4.9 mmol) and HATU (1260 mg, 3.3 mmol) after purification by flash chromatography (kp-NH, eluting with a gradient of 20-100% EtOAc/heptane), the title compound (363 mg, 43%) is a yellow oil. Was obtained as.

HPLCMS (Method A): [m/z]: 507.1 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(1-methyl-1H-pyrazol-4-yl)methyl]carbamoyl}-1 ,3-Thiazol-2-yl)ethyl]carbamate (62)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (2 ml). , 3-thiazole-4-carboxylic acid (8) (100 mg, 0.25 mmol), (1-methyl-1H-pyrazol-4-yl)methanamine (41 mg, 0.37 mmol), DIPEA (130 μl, 0.75 mmol). And HATU (142 mg, 0.37 mmol) after purification by flash column chromatography (eluting with a gradient of 0-20% MeOH/EtOAc) gave the title compound (125 mg, quantitative) as a yellow oil.

HPLC MS (Method A): [m/z]: 496.1 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6-methylpyridazin-3-yl)methyl]carbamoyl}-1,3- Thiazol-2-yl)ethyl]carbamate (63)

In a similar manner to General Procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (3 ml). , 3-Thiazol-4-carboxylic acid (8) (100 mg, 0.23 mmol, purity 92%), (6-methylpyridazin-3-yl)methanamine (42 mg, 0.34 mmol), DIPEA (119 μl, 0.69 mmol). ) And HATU (130 mg, 0.34 mmol) after purification by flash column chromatography (kp-NH, eluting with a gradient of 70-100% EtOAc/heptane), the crude title compound (99 mg, 67%, 79% purity). was gotten.

1H-NMR (CDCl ₃ , 500 MHz): d [ppm] = 10.50 (s, 1H), 8.28 (s, 1H), 7.92 (s, 1H), 7.72 (s, 1H). , 7.40-7.29 (m, 3H), 7.23 (dd, J=6.4, 2.8 Hz, 2H), 4.68 (s, 2H), 3.82 (s, 2H). , 3.24 (s, 2H), 2.73 (s, 2H), 2.71 (s, 3H), 1.36 (s, 9H)
HPLCMS (Method A): [m/z]: 508.10 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(1H-imidazol-2-ylmethyl)carbamoyl]-1,3-thiazol-2- Il}ethyl)carbamate (64)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (2 ml). , 3-Thiazol-4-carboxylic acid (8) (100 mg, 0.25 mmol), 1-(1H-imidazol-2-yl)methanamine (42 mg, 0.25 mmol), DIPEA (164 μl, 0.99 mmol) and HATU. After purification by flash column chromatography (kp-NH, gradient 0-5% MeOH/DCM) by (188 mg, 0.50 mmol), the title compound (65 mg, 54%) was obtained as a yellow oil.

HPLC MS (Method A): [m/z]: 482.25 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(morpholin-4-yl)pyridin-4-yl]methyl}carbamoyl )-1,3-Thiazol-2-yl]ethyl}carbamate (65)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (2 ml). , 3-Thiazol-4-carboxylic acid (8) (100 mg, 0.25 mmol), [3-(morpholin-4-yl)pyridin-4-yl]methanamine (48 mg, 0.25 mmol), DIPEA (164 μl, 0). .99 mmol) and HATU (189 mg, 0.50 mmol) and after purification by flash column chromatography (kp-NH, eluting with a gradient of 50-100% EtOAc/heptane), the title compound (112 mg, 78%) is a yellow solid. Was obtained as.

HPLC MS (Method A): [m/z]: 578.10 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(5-methylpyridin-2-yl)methyl]carbamoyl}-1,3- Thiazol-2-yl)ethyl]carbamate (66)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (2 ml). , 3-Thiazol-4-carboxylic acid (8) (100 mg, 0.20 mmol, purity 80%), 1-(5-methylpyridin-2-yl)methanamine (29 mg, 0.24 mmol), DIPEA (104 μl, 0). .60 mmol) and HATU (151 mg, 0.40 mmol) followed by flash column chromatography (kp-NH, eluting with a gradient of 0-100% EtOAc/heptane) to give the title compound (48 mg, 47%) as a colorless oil. Was obtained as.

HPLCMS (Method A): [m/z]: 507.1 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[6-(dimethylamino)pyridin-3-yl]methyl}carbamoyl)-1 ,3-Thiazol-2-yl]ethyl}carbamate (67)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (2 ml). ,3-Thiazol-4-carboxylic acid (8) (100 mg, 0.20 mmol, purity 80%), 5-(aminomethyl)-N,N-dimethylpyridin-2-amine (30 mg, 0.20 mmol), DIPEA. After purification by flash column chromatography (kp-NH, eluting with a gradient of 0-100% EtOAc/heptane) by (104 μl, 0.60 mmol) and HATU (151 mg, 0.40 mmol), the title compound (36 mg, 34%). ) Was obtained as a colorless oil.

HPLCMS (Method A): [m/z]: 536.35 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(2-methylpyridin-4-yl)methyl]carbamoyl}-1,3- Thiazol-2-yl)ethyl]carbamate (68)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (2 ml). , 3-Thiazol-4-carboxylic acid (8) (100 mg, 0.20 mmol, purity 80%), 1-(2-methylpyridin-4-yl)methanamine (36 mg, 0.30 mmol), DIPEA (104 μl, 0). .60 mmol) and HATU (151 mg, 0.40 mmol) by flash column chromatography (kp-NH, eluting with a gradient of 0-100% EtOAc/heptane) to give the title compound (36 mg, 36%) as a colorless oil. Was obtained as.

HPLC MS (Method A): [m/z]: 507.3 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]carbamoyl} -1,3-Thiazol-2-yl)ethyl]carbamate (69)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (2 ml). ,3-Thiazol-4-carboxylic acid (8) (100 mg, 0.20 mmol, purity 80%), 1-(1,5-dimethyl-1H-pyrazol-4-yl)methanamine (37 mg, 0.30 mmol), After purification by DIPEA (104 μl, 0.60 mmol) and HATU (151 mg, 0.40 mmol) by flash column chromatography (kp-NH, eluting with a gradient of 0-100% EtOAc/heptane) the title compound (74 mg, 73 %) was obtained as a colorless oil.

HPLCMS (Method A): [m/z]: 510.15 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl } Carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate (70)

In a similar manner to General Procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (3 ml). , 3-Thiazol-4-carboxylic acid (8) (100 mg, 0.236 mmol), 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methanamine hydrochloride (87 mg, 0.354 mmol). , DIPEA (0.21 ml, 1.18 mmol) and HATU (135 mg, 0.354 mmol) after purification by flash column chromatography (KP-NH, eluting with a gradient of 20-100% EtOAc/heptane). 216 mg, 69%, purity 45%) was obtained as a yellow oil. The title compound was used in the next step without further purification.

HPLC MS (Method A): [m/z]: 595.1 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-chloro-5-fluoropyridin-2-yl)methyl]carbamoyl}- 1,3-Thiazol-2-yl)ethyl]carbamate (71)

In a similar manner to General Procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (3 ml). , 3-thiazole-4-carboxylic acid (8) (100 mg, 0.236 mmol), (3-chloro-5-fluoropyridin-2-yl)methanamine hydrochloride (70 mg, 0.354 mmol), DIPEA (0.21 ml). , 1.18 mmol) and HATU (135 mg, 0.354 mmol) and after purification by flash column chromatography (KP-NH, eluting with a gradient of 20-100% EtOAc/heptane), the title compound (157 mg, 76%, pure). 62%) was obtained as a yellow oil. The title compound was used in the next step without further purification.

HPLC MS (Method A): [m/z]: 545.15 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(2-fluoropyridin-3-yl)methyl]carbamoyl}-1,3- Thiazol-2-yl)ethyl]carbamate (72)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (2 ml). , 3-Thiazol-4-carboxylic acid (8) (100 mg, 0.236 mmol, purity 95%), 1-(2-fluoropyridin-3-yl)methanamine (47.01 mg, 0.373 mmol), DIPEA(0. 0.13 ml, 0.745 mmol) and HATU (141.7 mg, 0.373 mmol) gave the title compound (0.359 g, quantitative) after evaporation of the solvent as a brown solid. The title compound was used in the next step without further purification.

HPLCMS (Method A): [m/z]: 511.10 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(2-methoxypyridin-4-yl)methyl]carbamoyl}-1,3- Thiazol-2-yl)ethyl]carbamate (73)

In a similar manner to General Procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (3 ml). , 3-Thiazol-4-carboxylic acid (8) (100 mg, 0.236 mmol, purity 95%), 1-(2-methoxypyridin-4-yl)methanamine (49 mg, 0.354 mmol), DIPEA (0.12 ml). , 0.708 mmol) and HATU (135 mg, 0.354 mmol), followed by purification by flash column chromatography (eluting with a gradient of 30-100% EtOAc/heptane) to give the title compound (104 mg, 81%, 96% purity). Obtained as a white solid.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=10.07 (s, 1H), 8.10 (d, J=5.3 Hz, 1H), 7.96 (s, 1H), 7. 73-7.66 (m, 2H), 7.41-7.37 (m, 1H), 7.25-7.22 (m, 2H), 6.85-6.82 (m, 1H), 6.69 (s, 1H), 4.62 (s, 2H), 4.56 (d, J=6.3 Hz, 2H), 3.91 (s, 3H), 3.78 (t, J= 6.6Hz, 2H), 3.24(t, J=6.2Hz, 2H), 1.39(s, 9H)
HPLC MS (Method A): [m/z]: 523.3 [M+H] ^+.
tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(4,6-dimethylpyridin-3-yl)methyl]carbamoyl}-1, 3-Thiazol-2-yl)ethyl]carbamate (74)

In a similar manner to General Procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (3 ml). ,3-Thiazol-4-carboxylic acid (8) (100 mg, 0.236 mmol, purity 95%), (4,6-dimethylpyridin-3-yl)methanamine dihydrochloride (B1) (93 mg, 0.354 mmol, Purity by flash column chromatography (eluting with a gradient of 0-15% MeOH/EtOAc) by 80% purity), DIPEA (0.206 ml, 1.18 mmol) and HATU (135 mg, 0.354 mmol) after purification of the title compound ( 77 mg, 63%) was obtained as a yellow oil.

HPLCMS (Method A): [m/z]: 521.05 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(4-methylpyridin-2-yl)methyl]carbamoyl}1,3-thiazole -2-yl)ethyl]carbamate (75)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (2 ml). ,3-Thiazol-4-carboxylic acid (8) (100 mg, 0.236 mmol, purity 95%), (4,6-dimethylpyridin-3-yl)methanamine dihydrochloride (93 mg, 0.354 mmol), DIPEA( 0.123 ml, 0.708 mmol) and HATU (135 mg, 0.354 mmol) by flash column chromatography (KP-NH, eluting with a gradient of 20-100% EtOAc/heptane followed by 0-20% MeOH/EtOAc). After purification by, the title compound (90 mg, 72%) was obtained as a yellow oil.

HPLC MS (Method A): [m/z]: 507.10 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-(5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl) -1,3-Thiazol-2-yl]ethyl}carbamate (76)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (2 ml). ,3-thiazole-4-carboxylic acid (8) (100 mg, 0.236 mmol, purity 95%), 5,6,7,8-tetrahydro-1,6-naphthyridine dihydrochloride (62 mg, 0.298 mmol), After purification by DIPEA (0.173 ml, 0.994 mmol) and HATU (151 mg, 0.398 mmol) by flash column chromatography (kp-NH, eluting with a gradient of 0-100% EtOAc/heptane), the title compound (90 mg , 72%) was obtained as a colorless oil.

HPLCMS (Method A): [m/z]: 519.15 [M+H] ^+.
tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3,5-difluoropyridin-2-yl)methyl]carbamoyl}-1, 3-Thiazol-2-yl)ethyl]carbamate (77)

In a similar manner to General Procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (3 ml). ,3-Thiazol-4-carboxylic acid (8) (100 mg, 0.236 mmol, purity 95%), (3,5-difluoropyridin-2-yl)methanamine dihydrochloride (65 mg, 0.298 mmol), DIPEA( After purification by flash column chromatography (kp-NH, eluting with a gradient of 0-100% EtOAc/heptane) with 0.173 ml, 0.994 mmol) and HATU (151 mg, 0.398 mmol), the title compound (112 mg, quant. Was obtained as a colorless oil.

HPLCMS (Method A): [m/z]: 528.10 [M+H] ^+.
tert-Butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridine-2 -Yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (78)

In a similar manner to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1 in DMF (2 ml). , 3-Thiazol-4-carboxylic acid (8) (15.94 mg, 0.04 mmol), (3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)methanamine (C3) (10 mg , 0.04 mmol), DIPEA (0.03 ml, 0.16 mmol) and HATU (30.13 mg, 0.08 mmol) after purification by flash column chromatography (eluting with a gradient of 0-100% EtOAc/heptane). The title compound (17.5 mg, 34%, purity 30%) was obtained as an orange oil.

HPLCMS (Method A): [m/z]: 637.15 [M+H] ^+.
tert-Butyl 2-{[(2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4- Iyl)formamido]methyl}piperidine-1-carboxylate (79)

In a similar manner to general procedure 6 for 2 hours at room temperature 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino in DMF (5 ml). ] Ethyl}-1,3-thiazole-4-carboxylic acid (8) (200 mg, 0.5 mmol), tert-butyl 2-(aminomethyl)piperidine-1-carboxylate (149 mg, 0.7 mmol), TEA( 66.16 μl, 0.5 mmol) and HATU (280 mg, 0.75 mmol) after flash column chromatography (eluting with a gradient of 0-100% EtOAc/heptane), followed by purification by basic preparative HPLC, the title compound. (50 mg, 17%) was obtained as an orange oil.

HPLC MS (Method A): [m/z]: 599.4 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-(pyridin-2-ylmethyl)-1,3-thiazole-4-carboxamide trihydrochloride (implementation Example compound No. 12)

In a similar manner to General Procedure 2 4M HCl in dioxane (11 ml) and tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N in dioxane (30 ml) for 16 hours at room temperature. -(2-{4-[(pyridin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate (9) (2.2 g, 4.47 mmol) with Et ₂ O(2 × 30 ml), after trituration from subsequent DCM (2 × 20ml) and _{Et 2 O (2 × 30ml)} , the title compound (HCl salt) (1.7g, 76%) as a yellow solid.

1H-NMR (DMSO-d6, 500MHz): d [ppm] = 10.39 (s, 1H), 9.68 (t, J = 6.0Hz, 1H), 8.86-8.75 (m, 1H), 8.44 (td, J=7.9, 1.5Hz, 1H), 8.30 (s, 1H), 7.96-7.84 (m, 2H), 7.76 (dt, J=6.5, 3.3 Hz, 2H), 7.44 (dq, J=6.5, 3.4 Hz, 2H), 4.86 (d, J=6.0 Hz, 2H), 4.76 (S, 2H), 3.66 (dt, J=38.8, 7.1Hz, 4H)
HPLC MS (Method C): [m/z]: 493.4 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-(thiophen-2-ylmethyl)-1,3-thiazole-4-carboxamide (Example compound 16) No.)

In a similar manner to General Procedure 7, tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(thiophene-2- After purification by preparative HPLC with ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate (12) (180 mg, 0.362 mmol) and 50% TFA in DCM (51 mg). , 34%, purity 98%) was obtained as a white oil.

1H-NMR (CDCl ₃ , 400 MHz): d[ppm]=8.05 (s, 1H), 7.59 (m, 3H), 7.24 (m, 2H), 7.21-7.19( dd, J=5.1, 1.2 Hz, 1H), 7.01 (m, 1H), 6.94 (m, 1H), 4.78 (d, J=6.0, 2H), 4. 15 (s, 2H), 3.27-3.07 (m, 4H)
HPLCMS (Method J): [m/z]: 398.5 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-methyl-N-phenyl-1,3-thiazole-4-carboxamide (Example Compound No. 19)

In a manner similar to general procedure 2, tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[methyl(phenyl)carbamoyl] at room temperature overnight. ]-1,3-Thiazol-2-yl}ethyl)carbamate (15) (110.12 mg, 0.224 mmol) and 50% TFA in DCM (10 ml) by flash column chromatography (0-10% MeOH in DCM). After purification by elution (gradient), the title compound (40 mg, 45%, 85% purity) was obtained as a white oil.

_{1H-NMR (CDCl 3, 400MHz} ): d [ppm] = 7.69 (bs, 2H), 7.29-7.21 (m, 5H), 7.10 (s, 2H), 4.28 ( s, 2H), 3.60-3.43 (m, 3H), 3.18 (bs, 2H), 3.05 (bs, 2H).
HPLCMS (Method J): [m/z]: 392.5 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-{[2-(pyrrolidin-1-yl)phenyl]methyl}-1,3-thiazole- 4-carboxamide (Example compound No. 21)

In a similar manner to General Procedure 2, tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-( Flash column chromatography by pyrrolidin-1-yl)phenyl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate (16) (100 mg, 0.178 mmol) and 50% TFA in DCM (8 ml). After purification by chromatography (eluting with a gradient of 5-7% MeOH in DCM), the title compound (70 mg, 69%, 82% purity) was obtained as a white oil.

1H-NMR (CDCl ₃ , 400 MHz): d[ppm]=7.94 (s, 1H), 7.85 (t, J=5.6 Hz, 1H), 7.53-7.47 (m, 2H). ), 7.24-7.16 (m, 2H), 7.12 (t, J=7.8Hz, 1H), 6.59 (d, J=7.5Hz, 1H), 6.48(s). , 1H), 6.43 (d, J=8.1 Hz, 1H), 4.53 (d, J=5.9 Hz, 2H), 4.14 (s, 2H), 3.21 (m, 4H) ), 3.12-3.05 (m, 4H), 2.00-1.90 (m, 4H)
HPLCMS (Method J): [m/z]: 461.6 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-(pyridin-3-ylmethyl)-1,3-thiazole-4-carboxamide trihydrochloride (Implementation (Example compound No. 35)

In a similar manner to General Procedure 2 for 18 hours at room temperature tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyridin-3- Ilmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate (22) (184 mg, 0.374 mmol) and 4M HCl in dioxane (15 ml) after precipitation with Et ₂ O as the tri-HCl salt. The title compound (80 mg, 53%) was obtained as a white solid.

1H-NMR (DMSO-d6, 400MHz): d [ppm] = 10.28 (bs, 3H), 9.64 (t, J = 6.2Hz, 1H), 8.90 (s, 1H), 8 .81 (d, J=5.4 Hz, 1H), 8.55 (d, J=8.1 Hz, 1H), 8.25 (s, 1H), 8.00 (dd, J=8.0, 5.7 Hz, 1 H), 7.73 (m, 2 H), 7.48-7.34 (m, 2 H), 4.71 (s, 2 H), 4.65 (d, J=6.2 Hz, 2H), 3.66 (t, J=6.6Hz, 2H), 3.57 (t, J=6.3Hz, 2H)
HPLCMS (Method J): [m/z]: 493.3 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-(pyridin-4-ylmethyl)-1,3-thiazole-4-carboxamide trihydrochloride (Implementation (Example compound #36)

In a similar manner to General Procedure 2 for 18 hours at room temperature tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyridin-4- Ilmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate (23) (145.8 mg, 0.296 mmol) and 4M HCl in dioxane (15 ml) after precipitation with Et ₂ O followed by the tri-HCl salt. The title compound (70 mg, 47%) was obtained as a white solid.

1H-NMR (DMSO, 400MHz): d [ppm] = 10.40 (bs, 3H), 9.69 (t, J = 6.2Hz, 1H), 8.83 (d, J = 6.7Hz, 2H), 8.28 (s, 1H), 7.98 (d, J=6.6Hz, 2H), 7.81-7.69 (m, 2H), 7.49-7.37 (m, 2H), 4.73 (d, J=5.1 Hz, 4H), 3.68 (t, J=6.5 Hz, 2H), 3.60 (t, J=6.4 Hz, 2H)
HPLCMS (Method J): [m/z]: 493.3 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1,3- Thiazole-4-carboxamide (Example compound No. 37)

In a similar manner to General Procedure 2 for 18 hours at room temperature tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[3-( Trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate (24) (86.33 mg, 0.154 mmol) and 4M HCl in dioxane (10 ml). After purification by flash column chromatography (eluting with a gradient of 10-15% MeOH in DCM), the title compound (25 mg, 35%) was obtained as a yellow oil.

1H-NMR (MeOD, 400 MHz): d[ppm]=8.62 (d, J=4.8 Hz, 1H), 8.13-8.09 (m, 1H), 8.08 (s, 1H). , 7.52-7.47 (m, 2H), 7.47-7.41 (m, 1H), 7.22-7.14 (m, 2H), 4.86 (s, 2H), 4 0.09 (s, 2H), 3.27 (t, J = 6.6Hz, 2H), 3.13 (t, J = 6.6Hz, 2H)
HPLCMS (Method J): [m/z]: 461.6 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-(5,6,7,8-tetrahydroquinolin-8-ylmethyl)-1,3-thiazole -4-carboxamide (Example compound No. 38)

In a similar manner to General Procedure 2 for 18 hours at room temperature tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(5,6,6. Flash with 7,8-tetrahydroquinolin-8-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate (25) (82.03 mg, 0.154 mmol) and 4M HCl in dioxane (10 ml). After purification by column chromatography (eluting with a gradient of 10-15% MeOH in DCM), the title compound (35 mg, 52%) was obtained as a yellow oil.

1H-NMR (MeOD, 400 MHz): d[ppm]=8.27 (d, J=3.6 Hz, 1H), 8.08 (s, 1H), 7.58 (d, J=7.6 Hz, 1H), 7.49 (m, 2H), 7.27-7.15 (m, 3H), 5.22-5.12 (m, 1H), 4.05 (s, 2H), 3.21. (T, J=6.7 Hz, 2H), 3.05 (t, J=6.4 Hz, 2H), 2.96-2.77 (m, 2H), 2.34-2.20 (m, 1H), 2.05-1.79 (m, 3H)
HPLCMS (Method J): [m/z]: 433.6 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl}-1,3- Thiazole-4-carboxamide trihydrochloride (Example compound No. 39)

In a manner similar to General Procedure 2, 4M HCl in dioxane (6.36 ml) was added to tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{ in dioxane (30 ml). 2-[4-({5H,6H,7H-Cyclopenta[b]pyridin-7-yl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate (26) (1.32g, 2.55mmol) ) And stirred at room temperature for 48 hours to give the title compound (1.03 g, 76%) after crystallization from DCM/MeOH.

1H-NMR (MeOD, 500MHz): d [ppm] = 8.56 (d, J = 5.8Hz, 1H), 8.52-8.48 (m, 1H), 8.31 (s, 1H). , 7.92 (dd, J=7.7, 6.0 Hz, 1H), 7.86 (dt, J=6.7, 3.3 Hz, 2H), 7.66 (dt, J=6.3). , 3.3Hz, 2H), 5.95(t, J=8.8Hz, 1H), 5.01(s, 2H), 3.87(t, J=6.2Hz, 2H), 3.71. -3.63 (m, 2H), 3.42-3.35 (m, 1H), 3.21 (dt, J=17.1, 8.7Hz, 1H), 2.86-2.77 ( m, 1H), 2.51 (dq, J=12.9, 9.2Hz, 1H)
HPLC MS (Method C): [m/z]: 419.05 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4- Carboxamide trihydrochloride (Example compound No. 40)

In a manner similar to General Procedure 2, 4M HCl in dioxane (16.57 ml, 66.26 mmol) was added to tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl) in dioxane (40 ml). -N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (27) (4.13 g, 6.63 mmol) ) And stirred at room temperature for 16 hours to give the title compound (3.04 g, 88%) as a white solid after precipitation from Et ₂ O (100 ml).

1H-NMR (MeOD, 500 MHz): d[ppm]=8.47 (d, J=5.1 Hz, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 7.84. (Dd, J=6.1, 3.1 Hz, 2H), 7.76 (s, 1H), 7.62 (dd, J=6.1, 3.0 Hz, 2H), 4.99 (s, 2H), 4.95 (s, 2H), 3.84 (t, J = 6.2Hz, 2H), 3.65 (t, J = 6.2Hz, 2H)
HPLCMS (Method D): [m/z]: 411.1 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(6-methylpyridin-2-yl)methyl]-1,3-thiazol-4- Carboxamide (Example compound No. 42)

In a similar manner to General Procedure 2, tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6-methyl Pyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (29) (79.5 mg, 0.157 mmol) and 4M HCl in dioxane (15 ml) for flash column chromatography. After purification by (eluting with a gradient of 10-15% MeOH in DCM), the title compound (25.5 mg, 36%) was obtained as a pale yellow oil.

1H-NMR (MeOD, 400MHz): d [ppm] = 8.09 (s, 1H), 7.63 (t, J = 7.7Hz, 1H), 7.50 (m, 2H), 7.23. -7.17 (m, 3H), 7.15 (m, 2H), 4.63 (s, 2H), 4.08 (s, 2H), 3.26 (t, J=6.7Hz, 2H ), 3.11 (t, J=6.6 Hz, 2H), 2.50 (s, 3H)
HPLCMS (Method J): [m/z]: 405.5 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(5-fluoropyridin-2-yl)methyl]-1,3-thiazole-4- Carboxamide (Example compound No. 43)

In a similar manner to General Procedure 2, tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(5-fluoro Flash column chromatography by pyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (30) (80.2 mg, 0.157 mmol) and 4M HCl in dioxane (15 ml). After purification by (eluting with a gradient of 10-15% MeOH in DCM), the title compound (12.5 mg, 17%) was obtained as a pale yellow oil.

1H-NMR (MeOD, 400 MHz): d[ppm]=8.36 (d, J=2.6 Hz, 1H), 8.08 (s, 1H), 7.59-7.46 (m, 3H). , 7.42 (m, 1H), 7.20 (m, 2H), 4.66 (s, 2H), 4.08 (s, 2H), 3.26 (t, J=6.5Hz, 2H ), 3.11 (t, J=6.5 Hz, 2H)
HPLCMS (Method J): [m/z]: 411.5 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-(pyrimidin-4-ylmethyl)-1,3-thiazole-4-carboxamide (Example Compound No. 44)

In a similar manner to general procedure 2 for 4 hours at room temperature tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyrimidine-4- Illuminyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate (31) (75 mg, 0.152 mmol) and 4M HCl in dioxane (2 ml) by flash column chromatography (gradient 8% MeOH in DCM). After purification by elution), the title compound (22 mg, 37%) was obtained as a yellow solid.

1H-NMR (MeOD, 400 MHz): d[ppm]=9.05 (d, J=1.1 Hz, 1H), 8.67 (d, J=5.3 Hz, 1H), 8.12 (s, 1H), 7.51 (dd, J=6.0, 3.2 Hz, 2H), 7.46 (d, J=5.3 Hz, 1H), 7.26-7.18 (m, 2H), 4.68 (s, 2H), 4.10 (s, 2H), 3.28 (t, J=6.5Hz, 2H), 3.14 (t, J=6.6Hz, 2H)
HPLCMS (Method J): [m/z]: 394.4 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(5-methoxypyridin-2-yl)methyl]-1,3-thiazole-4- Carboxamide (Example compound No. 45)

In a similar manner to General Procedure 2, tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(5-methoxy Pyridine-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (32) (80 mg, 0.153 mmol) and 4M HCl in dioxane (2 ml) by flash column chromatography (DCM). After purification by elution with a gradient of 8% MeOH in), the title compound (53 mg, 82%) was obtained as a yellow solid.

1H-NMR (MeOD, 400 MHz): d[ppm]=8.17-8.13 (m, 1H), 8.08 (s, 1H), 7.54-7.47 (m, 2H), 7 .35-7.31 (m, 2H), 7.25-7.18 (m, 2H), 4.61 (s, 2H), 4.07 (d, J=8.0Hz, 2H), 3 .84 (s, 3H), 3.26 (t, J=6.6Hz, 2H), 3.11 (t, J=6.6Hz, 2H)
HPLCMS (Method J): [m/z]: 423.4 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-(pyrazin-2-ylmethyl)-1,3-thiazole-4-carboxamide (Example Compound 46 No.)

In a similar manner to General Procedure 2, tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyrazin-2- Illuminyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate (33) (70 mg, 0.142 mmol) and 4M HCl in dioxane (2 ml) by flash column chromatography (gradient of 8% MeOH in DCM). After purification by elution), the title compound (30 mg, 53.7%) was obtained as a brown solid.

1H-NMR (MeOD, 400 MHz): d[ppm]=8.63 (s, 1H), 8.56-8.51 (m, 1H), 8.48 (d, J=2.6 Hz, 1H). , 8.12 (s, 1H), 7.52 (dd, J=6.0, 3.2 Hz, 2H), 7.22 (dd, J=6.1, 3.1 Hz, 2H), 4. 74 (s, 2H), 4.13 (s, 2H), 3.28 (t, J=6.5Hz, 2H), 3.17 (t, J=6.5Hz, 2H)
HPLC MS (Method I): [m/z]: 394.4 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(6-oxo-1,6-dihydropyridin-2-yl)methyl]-1,3 -Thiazole-4-carboxamide (Example compound No. 47)

In a similar manner to General Procedure 2, tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6-oxo -1,6-Dihydropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (34) (70 mg, 0.138 mmol) and 4M HCl in dioxane HCl (2 ml). After purification by flash column chromatography (eluting with a gradient of 8% MeOH in DCM), the title compound (30 mg, 53%) was obtained as a yellow solid.

1H-NMR (MeOD, 400 MHz): d[ppm]=8.12 (s, 1H), 7.51 (m, 3H), 7.22 (dd, J=6.0, 3.2 Hz, 2H). , 6.42 (d, J=9.1 Hz, 1H), 6.30 (d, J=6.9 Hz, 1H), 4.44 (s, 2H), 4.09 (s, 2H), 3 .27 (t, J=6.7 Hz, 2H), 3.12 (t, J=6.7 Hz, 2H)
HPLCMS (Method J): [m/z]: 409.4 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(6-cyanopyridin-3-yl)methyl]-1,3-thiazol-4- Carboxamide (Example Compound No. 56) and 5-{[(2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-1,3-thiazol-4-yl) Formamide]methyl}pyridine-2-carboxamide (Example compound No. 54)

In a manner similar to general procedure 2, tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6-carbamoyl) at room temperature for 18 hours. Pyridin-3-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (35) and tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N A mixture of -[2-(4-{[(6-cyanopyridin-3-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (36) (80 mg, 0.155 mmol) and 4M HCl in dioxane (3 ml) gave two products. Formamide (Example Compound #54) (16 mg, 23%) was isolated after flash column chromatography (DCM/MeOH, eluting with a gradient of 9:1). The crude nitrile (Example Compound #56) was also isolated and further purified by basic preparative HPLC to give the required product as a brown solid (24 mg, 37%).

Formamide: 1H-NMR (Methanol-d4, 400MHz): d [ppm] = 8.49 (t, J = 10.2Hz, 1H), 7.99 (s, 1H), 7.94 (t, J = 10.0 Hz, 1H), 7.78 (dt, J=8.1, 4.0 Hz, 1H), 7.46-7.34 (m, 2H), 7.11 (dd, J=6.0). , 3.1Hz, 2H), 4.56 (d, J = 14.2Hz, 2H), 4.02 (d, J = 8.0Hz, 2H), 3.19 (m, 4H), 3.06 (T, J=6.5Hz, 2H)
HPLC MS (Method I): [m/z]: 436.5 [M+H] ^+.
Nitrile: 1H-NMR (DMSO-d6, 500MHz): d [ppm] = 12.18 (s, 1H), 9.08 (t, J = 6.2Hz, 1H), 8.70 (s, 1H). , 8.14 (s, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.92 (dd, J=8.1, 2.0 Hz, 1H), 7.48 (d, J=29.4 Hz, 2H), 7.12 (d, J=4.7 Hz, 2H), 4.54 (d, J=6.2 Hz, 2H), 4.10 (d, J=5.2 Hz) , 1H), 3.96 (s, 2H), 3.18-3.15 (m, 2H), 2.98 (d, J=6.6Hz, 2H).
HPLC MS (Method I): [m/z]: 418.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3,5-dimethylpyridin-2-yl)methyl]-1,3-thiazole- 4-carboxamide (Example compound No. 57)

In a similar manner to general procedure 2 for 21 h at 40° C. in tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4- {[(3,5-Dimethylpyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (37) (198 mg, 0.36 mmol) and 12M HCl (0.307 ml, (8.42 mmol) gave the title compound (90 mg, 59%) as a yellow solid after purification by neutral preparative HPLC.

1H-NMR (DMSO-d6,500MHz): d[ppm]=12.17(s,1H),8.71(t,J=4.8Hz,1H),8.16(s,1H),8 .14 (s, 1H), 7.51 (s, 1H), 7.42 (s, 2H), 7.12 (d, J=4.9 Hz, 2H), 4.52 (d, J=4) 9.9 Hz, 2H), 3.97 (s, 2H), 3.17 (d, J=4.9 Hz, 2H), 2.98 (t, J=6.8 Hz, 2H), 2.27 (s. , 3H), 2.24 (s, 3H)
HPLCMS (Method B): [m/z]: 421.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-(pyrimidin-2-ylmethyl)-1,3-thiazole-4-carboxamide (Example Compound 61 No.)

In a similar manner to general procedure 2 tert-butyl 2-({[(tert-butoxy)carbonyl](2-{4-[(pyrimidin-2-ylmethyl)) in MeOH (2 ml) at 40° C. for 24 hours. Carbamoyl]-1,3-thiazol-2-yl}ethyl)amino}methyl)-1H-1,3-benzodiazol-1-carboxylate (38) (86 mg, 0.145 mmol) and 12M HCl (0. After purification by flash column chromatography (gradient 100% DCM, 90% DCM: 10% MeOH and 90% DCM: 10% methanolic ammonia), followed by basic preparative HPLC, by 282 ml, 3.378 mmol). The title compound (24 mg, 42%) was obtained as a brown solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.18 (s, 1H), 8.75 (dd, J=10.2, 5.4 Hz, 3H), 8.13 (s, 1H), 7.48 (d, J=36.0 Hz, 2H), 7.39 (t, J=4.9 Hz, 1H), 7.19-7.03 (m, 2H), 4.66( d, J=5.8Hz, 2H), 3.97(s, 2H), 3.20(t, J=6.8Hz, 2H), 2.99(t, J=6.8Hz, 2H), 2.66 (s, 1H)
HPLC MS (method B): [m/z]: 394.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-{[2-(4-methylpiperazin-1-yl)phenyl]methyl}-1,3 -Thiazole-4-carboxamide (Example compound No. 68)

In a similar manner to general procedure 2 for 16 h at 50° C. in dioxane (0.5 ml) tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[ 4-({[2-(4-methylpiperazin-1-yl)phenyl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate (39) (13.4 mg, 0.02 mmol) and 4M HCl in dioxane (55.1 μl) gave the title compound (11.5 mg, 85%) as a white solid after trituration with DCM.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.28 (s, 1H), 7.88 (dt, J=6.6, 3.3Hz, 2H), 7.69 (dt, J=6.3, 3.3Hz, 2H), 7.45(t, J=7.6Hz, 1H), 7.33(d, J=6.7Hz, 2H), 7.20-7.14. (M, 1H), 5.06 (s, 2H), 4.78 (s, 2H), 3.87 (t, J=6.2Hz, 2H), 3.72-3.59 (m, 4H) ), 3.49 (t, J=10.5 Hz, 2H), 3.37 (s, 2H), 3.27 (d, J=11.0 Hz, 2H), 3.02 (s, 3H)
HPLCMS (Method D): [m/z]: 490.3 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(2,6-difluorophenyl)methyl]-1,3-thiazole-4-carboxamide( Example compound No. 69)

In a similar manner to General Procedure 2 for 16 hours at room temperature in tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{ in dioxane (2 ml). Preparative HPLC with [(2,6-difluorophenyl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (40) (90 mg, 0.17 mmol) and 4M HCl in dioxane (427 μl). After purification by, the title compound (15 mg, 20.6%) was obtained as an off-white solid.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.06(s, 1H), 7.53(dd, J=5.8, 3.2Hz, 2H), 7.34(tt, J=8.4, 6.5 Hz, 1H), 7.29-7.16 (m, 2H), 7.03-6.88 (m, 2H), 4.68 (s, 2H), 4. 07 (s, 2H), 3.23 (t, J = 6.6Hz, 2H), 3.09 (t, J = 6.6Hz, 2H)
HPLC MS (Method A): [m/z]: 428.1 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-{[2-(dimethylamino)phenyl]methyl}-1,3-thiazole-4-carboxamide (Example compound No. 70)

In a similar manner to general procedure 2 for 16 hours at 50° C. in tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4- ({[2-(Dimethylamino)phenyl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate (41) (73 mg, 0.14 mmol) and 4M HCl in dioxane (341 [mu]l) was added. After purification by preparative HPLC, the title compound (8.7 mg, 14%) was obtained.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.08 (s, 1H), 7.53 (dd, J=5.9, 3.2Hz, 2H), 7.29-7. 14 (m, 5H), 7.02 (td, J=7.4, 1.1 Hz, 1H), 4.68 (s, 2H), 4.08 (s, 2H), 3.25 (t, J=6.7 Hz, 2H), 3.11 (t, J=6.8 Hz, 2H), 2.67 (s, 6H)
HPLC MS (method D): [m/z]: 435.3 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(2-cyanophenyl)methyl]-1,3-thiazole-4-carboxamide (Example Compound 71)

In a similar manner to general procedure 2 for 12 hours at 50° C. in tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4- By [[(2-cyanophenyl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (42) (54 mg, 0.1 mmol) and 4M HCl in dioxane (261 μl) by preparative HPLC. After purification, the title compound (8 mg, 18%) was obtained as a yellow solid.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.11 (s, 1H), 7.74-7.69 (m, 1H), 7.60 (td, J=7.8, 1.2 Hz, 1H), 7.56-7.50 (m, 3H), 7.43 (t, J=7.6Hz, 1H), 7.25-7.19 (m, 2H), 4. 78 (s, 2H), 4.09 (s, 2H), 3.27 (t, J=6.6Hz, 2H), 3.13 (t, J=6.6Hz, 2H)
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-{[2-(trifluoromethoxy)phenyl]methyl}-1,3-thiazol-4- Carboxamide (Example compound No. 72)

In a similar manner to general procedure 2 for 16 hours at room temperature in tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-(in MeOH (2 ml). {[2-(Trifluoromethoxy)phenyl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate (43) (110 mg, 0.191 mmol), 12M HCl (0.317 ml, 4.458 mmol). ) Afforded the title compound (41 mg, 45%) as a white solid after purification by basic preparative HPLC.

1H-NMR (DMSO-d6, 500MHz): d [ppm] = 12.19 (s, 1H), 8.88 (t, J = 6.2Hz, 1H), 8.15 (s, 1H), 7 .48 (d, J=31.2 Hz, 2H), 7.42-7.30 (m, 4H), 7.13 (d, J=4.9 Hz, 2H), 4.53 (d, J= 6.3 Hz, 2H), 3.97 (s, 2H), 3.19 (t, J=6.8 Hz, 2H), 2.99 (t, J=6.8 Hz, 2H)
HPLC MS (Method A): [m/z]: 476.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-{[2-(difluoromethoxy)phenyl]methyl}-1,3-thiazole-4-carboxamide (Example compound No. 74)

In a similar manner to General Procedure 2, crude tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4, in MeOH (5 ml) at 50° C. for 2 hours. -({[2-(difluoromethoxy)phenyl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate (45) (470 mg), 12M HCl (5 ml) by flash column chromatography (KP. After -NH, elution with a gradient of 0-15% MeOH/DCM) followed by purification by preparative HPLC, the title compound (56 mg, 35%) was obtained as a pale yellow solid.

1H-NMR (DMSO-d6, 500MHz): d [ppm] = 12.18 (s, 1H), 8.79 (t, J = 6.2Hz, 1H), 8.13 (s, 1H), 7 .47 (s, 2H), 7.35-7.28 (m, 2H), 7.25-7.06 (m, 5H), 4.48 (d, J=6.2Hz, 2H), 3 .96 (s, 2H), 3.22-3.17 (m, 2H), 2.98 (t, J=6.8Hz, 2H)
HPLCMS (Method D): [m/z]: 458.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-{[2-(morpholine-4-sulfonyl)phenyl]methyl}-1,3-thiazole- 4-carboxamide (Example compound No. 75)

In a similar manner to General Procedure 2, crude tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4, in MeOH (5 ml) at 50° C. for 2 hours. Flash column chromatography by -({[2-(morpholine-4-sulfonyl)phenyl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate (46) (440 mg), 12M HCl (5 ml). After chromatography (KP-NH, eluting with a gradient of 0-15% MeOH/DCM), followed by purification by preparative HPLC, the title compound (67 mg, 42%) was obtained as a pale yellow solid.

1H-NMR (DMSO-d6, 500MHz): d [ppm] = 12.19 (s, 1H), 8.88 (t, J = 6.3Hz, 1H), 8.17 (s, 1H), 7 .84 (d, J=7.9 Hz, 1H), 7.66 (t, J=7.6 Hz, 1H), 7.50 (dd, J=11.8, 7.7 Hz, 4H), 7. 17-7.06 (m, 2H), 4.81 (d, J=6.2Hz, 2H), 3.97 (s, 2H), 3.70-3.61 (m, 4H), 3. 20 (t, J=6.8 Hz, 2H), 3.10-3.04 (m, 4H), 2.99 (t, J=6.7 Hz, 2H)
HPLCMS (Method D): [m/z]: 541.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[2-(pyridin-2-yl)ethyl]-1,3-thiazole-4-carboxamide (Example compound No. 76)

In a manner similar to General Procedure 2, dioxane (2 ml) was added to tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[2-( Pyridin-2-yl)ethyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (47) (52 mg, 0.103 mmol) and 4M HCl in dioxane (257 μl, 1.03 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours to give the title compound (11 mg, 26%) as a tan solid after purification by neutral preparative HPLC.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.44 (ddd, J=5.0, 1.7, 0.8Hz, 1H), 8.03 (s, 1H), 7. 72 (td, J=7.7, 1.8 Hz, 1H), 7.55 (dd, J=5.8, 3.2 Hz, 2H), 7.33 (d, J=7.8 Hz, 1H) , 7.29-7.19 (m, 3H), 4.09 (s, 2H), 3.74 (t, J=7.1 Hz, 2H), 3.25 (t, J=6.7 Hz, 2H), 3.13-3.05 (m, 4H)
HPLCMS (Method B): [m/z]: 407.1 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-(3-fluoropyridin-2-yl)-1,3-thiazol-4-carboxamide (implementation (Example compound No. 77)

In a manner similar to General Procedure 2, dioxane (4 ml) was added to crude tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(3- Add fluoropyridin-2-yl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate (48) (705 mg) and 4M HCl in dioxane (1.56 ml, 6.24 mmol). The reaction mixture was stirred at room temperature for 16 hours to give the title compound (10 mg, 3.9%) as a tan solid after purification by neutral preparative HPLC.

1H-NMR (Methanol-d4,500MHz): d [ppm] = 8.37 (s, 1H), 8.29 (dd, J = 4.7, 1.0Hz, 1H), 7.75 (ddd, J=9.8, 8.4, 1.4 Hz, 1H), 7.52 (dd, J=6.1, 3.2 Hz, 2H), 7.41 (ddd, J=8.4, 4. 7, 3.8 Hz, 1H), 7.24 (dd, J=6.1, 3.2 Hz, 2H), 4.44 (s, 2H), 3.56-3.46 (m, 4H)
HPLCMS (Method D): [m/z]: 397.1 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoro-6-methylpyridin-2-yl)methyl]-1,3- Thiazole-4-carboxamide (Example compound No. 79)

In a manner similar to General Procedure 2, 4M HCl in dioxane (0.36 ml) was added to tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4- {[(3-Fluoro-6-methylpyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (50) (76 mg, 0.14 mmol) in dioxane (2 ml). After addition to the solution and stirring the mixture at room temperature for 16 hours, the title compound (24 mg, 39%) was obtained as a colorless oil after purification by basic preparative HPLC.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.09 (s, 1H), 7.55-7.42 (m, 3H), 7.29-7.14 (m, 3H). , 4.71 (d, J=1.7 Hz, 2H), 4.09 (s, 2H), 3.27 (t, J=6.7 Hz, 2H), 3.14 (t, J=6. 7Hz, 2H), 2.45 (s, 3H)
HPLC MS (Method D): [m/z]: 425.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[1-(pyridin-2-yl)ethyl]-1,3-thiazole-4-carboxamide (Example compound No. 80)

In a manner similar to General Procedure 2, 4M HCl in dioxane (0.39 ml, 1.56 mmol) was added to tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2. Solution of -(4-{[1-(pyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (51) (78 mg, 0.15 mmol) in dioxane (2 ml). Was added to the mixture and the mixture was stirred at room temperature for 16 hours to give the title compound (15 mg, 23%) as a colorless oil after purification by basic preparative HPLC.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.48 (ddd, J=4.9, 1.7, 0.9Hz, 1H), 8.08 (s, 1H), 7. 79 (td, J=7.8, 1.7 Hz, 1H), 7.54 (dd, J=5.7, 3.2 Hz, 2H), 7.45 (d, J=7.8 Hz, 1H) , 7.29 (ddd, J=7.5, 4.9, 1.1 Hz, 1H), 7.26-7.18 (m, 2H), 5.25 (d, J=7.0 Hz, 1H) ), 4.11 (s, 2H), 3.29 (t, J=6.7Hz, 2H), 3.16-3.12 (m, 2H), 1.57 (d, J=7.0Hz). , 3H)
HPLC MS (Method D): [m/z]: 407.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1,3- Thiazole-4-carboxamide (Example compound 81)

In a manner similar to general procedure 2, 4M HCl in dioxane (0.41 ml, 1.64 mmol) was added to tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2. Dioxane of -[4-({[6-(trifluoromethyl)pyridin-3-yl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate (52) (92 mg, 0.16 mmol) Add to solution in (2 ml) and stir the mixture at room temperature for 16 h to give the title compound (21 mg, 27%) as a colorless oil after purification by basic preparative HPLC.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.71 (d, J=1.5Hz, 1H), 8.11 (s, 1H), 8.00 (dd, J=8. 1,1.5 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.53 (dd, J=5.8, 3.2 Hz, 2H), 7.28-7.14 (M, 2H), 4.68 (s, 2H), 4.09 (s, 2H), 3.27 (t, J=6.7Hz, 2H), 3.12 (t, J=6.7Hz) , 2H)
HPLCMS (Method D): [m/z]: 461.1 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-chloropyridin-2-yl)methyl]-1,3-thiazole-4- Carboxamide (Example compound No. 82)

In a similar manner to general procedure 2 for 4 hours at 50° C. in tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-( in MeOH (1.6 ml). 4-{[(3-chloropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (53) (161 mg, 0.363 mmol) and 12M HCl (1.6 ml, (19.2 mmol) afforded the title compound (72 mg, 54%) as a white solid after purification by basic preparative HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.22 (s, 1H), 8.71 (t, J=5.5 Hz, 1H), 8.47 (dd, J=4. 7, 1.3 Hz, 1 H), 8.15 (s, 1 H), 7.95 (dd, J=8.1, 1.3 Hz, 1 H), 7.51 (s, 1 H), 7.45 ( s, 1H), 7.37 (dd, J=8.1, 4.7 Hz, 1H), 7.12 (d, J=4.8 Hz, 2H), 4.67 (d, J=5.5 Hz) , 2H), 3.97 (s, 2H), 3.20 (t, J = 6.8Hz, 2H), 2.98 (t, J = 6.8Hz, 2H).
HPLCMS (Method D): [m/z]: 427.1 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(2-oxo-1,2-dihydropyridin-3-yl)methyl]-1,3 -Thiazole-4-carboxamide (Example compound No. 83)

In a manner similar to general procedure 2, crude tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4, at 50° C. for 4 hours in MeOH (2 ml). -({[2-(tert-Butoxy)pyridin-3-yl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate (54) (205 mg, 0.36 mmol) and 12M HCl (2 ml). ) Afforded the title compound (66 mg, 44%) as a pale yellow solid after purification by basic preparative HPLC.

1H-NMR (DMSO-d6, 500MHz): d [ppm] = 12.17 (br s, 1H), 11.65 (br s, 1H), 8.59 (t, J = 6.0Hz, 1H). , 8.11 (s, 1H), 7.48 (s, 2H), 7.32-7.26 (m, 1H), 7.24 (d, J=6.7Hz, 1H), 7.12. (Dd, J=6.0, 3.1 Hz, 2H), 6.15 (t, J=6.6 Hz, 1H), 4.22 (d, J=6.0 Hz, 2H), 3.96( s, 2H), 3.21-3.14 (m, 2H), 2.97 (t, J=6.8Hz, 2H).
HPLC MS (method D): [m/z]: 409.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(1-methyl-1H-imidazol-5-yl)methyl]-1,3-thiazole -4-carboxamide (Example compound No. 84)

In a similar manner to General Procedure 2 for 2 hours at room temperature in tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{ in dioxane (7 ml). [(1-Methyl-1H-imidazol-5-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (55) (148 mg, 0.3 mmol) and 4M HCl to a basic content. After purification by preparative HPLC, the title compound (58 mg, 49%) was obtained as a colorless glass.

1H-NMR (DMSO-d6, 500MHz): d[ppm]=8.66(t, J=6.0Hz, 1H), 8.13(s, 1H), 7.60-7.31(m, 3H), 7.28-6.97 (m, 2H), 6.79 (s, 1H), 4.41 (d, J=6.0Hz, 2H), 3.96 (s, 2H), 3 .60 (s, 3H), 3.16 (t, J=6.8Hz, 2H), 2.97 (t, J=6.8Hz, 2H)
HPLCMS (Method B): [m/z]: 396.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-(1,3-oxazol-2-ylmethyl)-1,3-thiazole-4-carboxamide( Example compound No. 85)

In a manner similar to General Procedure 2, 4M HCl in dioxane (0.49 ml, 1.96 mmol) was added to tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2 -{4-[(1,3-Oxazol-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate (56) (95 mg, 0.196 mmol) in dioxane (2 ml) in solution. Upon addition and stirring of the mixture at room temperature for 3 hours, the title compound (13 mg, 17%) was obtained as a pale yellow oil after purification by neutral preparative HPLC.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.11 (s, 1H), 7.87 (d, J=0.8Hz, 1H), 7.54 (dd, J=5. 9, 3.2 Hz, 2H), 7.27-7.18 (m, 2H), 7.13 (d, J=0.8Hz, 1H), 4.70 (s, 2H), 4.10 ( s, 2H), 3.27 (t, J=6.6Hz, 2H), 3.13 (t, J=6.6Hz, 2H)
HPLCMS (Method D): [m/z]: 383.1 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-1,3-thiazole -4-carboxamide (Example compound No. 86)

In a manner similar to general procedure 2, 4M HCl in dioxane (0.27 ml, 1.08 mmol) was added to tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2. -(4-{[(1-Methyl-1H-pyrazol-3-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (57) (53 mg, 0.11 mmol) in dioxane ( (2 ml) in water at room temperature for 3 hours to give the title compound (16 mg, 38%) as a clear oil after purification by neutral preparative HPLC.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.08 (s, 1H), 7.57-7.46 (m, 3H), 7.28-7.15 (m, 2H). , 6.22 (d, J=2.2 Hz, 1H), 4.55 (s, 2H), 4.08 (s, 2H), 3.84 (s, 3H), 3.25 (t, J =6.7 Hz, 2H), 3.10 (t, J=6.7 Hz, 2H)
HPLCMS (Method D): [m/z]: 396.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-(pyridazin-3-ylmethyl)-1,3-thiazole-4-carboxamide (Example Compound 87 No.)

In a manner similar to general procedure 2, 4M HCl in dioxane (0.51 ml, 2.04 mmol) was added to tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2 -{4-[(Pyridazin-3-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate (58) (101 mg, 0.2 mmol) in dioxane (2 ml) at 50° C. Upon addition over time, the title compound (15 mg, 19%) was obtained as a tan solid after purification by neutral preparative HPLC.

1H-NMR (Methanol-d4,500MHz): d[ppm]=9.10 (dd, J=4.8, 1.7Hz, 1H), 8.12 (s, 1H), 7.76-7. 64 (m, 2H), 7.53 (dd, J=6.0, 3.2 Hz, 2H), 7.22 (dd, J=6.0, 3.2 Hz, 2H), 4.89 (s , 2H), 4.10 (s, 2H), 3.28 (t, J=6.6 Hz, 2H), 3.13 (t, J=6.6 Hz, 2H).
HPLCMS (Method D): [m/z]: 394.1 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(1-methyl-1H-pyrazol-5-yl)methyl]-1,3-thiazole -4-carboxamide (Example compound No. 88)

In a manner similar to general procedure 2, 4M HCl in dioxane (0.26 ml, 1.04 mmol) was added to tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2. -(4-{[(1-Methyl-1H-pyrazol-5-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (59) (51 mg, 0.103 mmol) in dioxane ( (2 ml) in solution at 50° C. for 1 h to give the title compound (12 mg, 30%) as an orange oil after purification by neutral preparative HPLC.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.10 (s, 1H), 7.53 (dd, J=6.0, 3.2Hz, 2H), 7.36 (d, J=1.9 Hz, 1H), 7.23 (dd, J=6.0, 3.2 Hz, 2H), 6.25 (d, J=1.9 Hz, 1H), 4.63 (s, 2H ), 4.08 (s, 2H), 3.89 (s, 3H), 3.26 (t, J=6.7Hz, 2H), 3.11 (t, J=6.7Hz, 2H).
HPLCMS (Method D): [m/z]: 396.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-4-yl)methyl]-1,3-thiazol-4- Carboxamide (Example compound No. 89)

In a similar manner to general procedure 2 for 2 hours at 50° C. in tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-( in MeOH (1.4 ml). 4-{[(3-fluoropyridin-4-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (60) (137 mg, 0.191 mmol, 71% purity) and 12M HCl( 1.4 ml, 16.8 mmol) afforded the title compound (46 mg, 59%) as a pale yellow solid after purification by neutral preparative HPLC.

1H-NMR (DMSO-d6, 500MHz): d [ppm] = 12.18 (s, 1H), 8.99 (t, J = 6.1Hz, 1H), 8.49 (d, J = 1. 6 Hz, 1 H), 8.35 (d, J=4.8 Hz, 1 H), 8.15 (s, 1 H), 7.48 (br s, 2 H), 7.35-7.26 (m, 1 H). ), 7.12 (d, J=3.5 Hz, 2H), 4.52 (d, J=6.1 Hz, 2H), 3.97 (s, 2H), 3.19 (t, J=6). 2.8 Hz, 2H), 2.98 (t, J=6.8 Hz, 2H)
HPLCMS (Method B): [m/z]: 411.1 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-methylpyridin-4-yl)methyl]-1,3-thiazol-4- Carboxamide trihydrochloride (Example compound No. 90)

In a manner similar to General Procedure 2, 4M HCl in dioxane (1.8 ml) was added to tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4- {[(3-Methylpyridin-4-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (61) (363 mg, 0.72 mmol) in dioxane (5 ml) at room temperature. Addition for 16 hours gave the title compound (203 mg, 55%) as a white solid. The solid, obtained from precipitation from DCM / MeOH was added heptane and washed with Et ₂ O and subsequently.

1H-NMR (methanol-d4, 500 MHz): d[ppm]=8.69 (s, 1H), 8.60 (d, J=6.1 Hz, 1H), 8.30 (s, 1H), 8 0.000 (d, J=6.1 Hz, 1H), 7.83 (dt, J=6.5, 3.3 Hz, 2H), 7.61 (dt, J=6.5, 3.3 Hz, 2H) ), 5.00 (s, 2H), 3.89 (t, J=6.3 Hz, 2H), 3.69 (t, J=6.3 Hz, 2H), 2.63 (s, 3H)( (CH ₂ signal is unclear depending on the solvent)
HPLC MS (method B): [m/z]: 407.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-1,3-thiazole -4-carboxamide (Example compound No. 91)

In a similar manner to general procedure 2 for 2 hours at 50° C. in tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4- {[(1-Methyl-1H-pyrazol-4-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (62) (125 mg, 0.25 mmol) and 12M HCl (0.49 ml). (5.88 mmol) afforded the title compound (42 mg, 42%) as a yellow/brown solid after purification by basic preparative HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.16 (s, 1H), 8.55 (t, J=6.0 Hz, 1H), 8.08 (s, 1H), 7 .55 (s, 1H), 7.48 (d, J=38.4 Hz, 2H), 7.32 (s, 1H), 7.20-7.03 (m, 2H), 4.25 (d). , J=6.0 Hz, 2H), 3.95(s, 2H), 3.76(s, 3H), 3.15(t, J=6.8Hz, 2H), 2.95(t, J =6.8Hz, 2H)
HPLCMS (Method D): [m/z]: 396.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(6-methylpyridazin-3-yl)methyl]-1,3-thiazol-4- Carboxamide (Example compound No. 93)

In a similar manner to General Procedure 2 for 2 hours at 50° C. in tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4- {[(6-Methylpyridazin-3-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (63) (99 mg, 0.154 mmol, purity 79%) and 12M HCl (1 ml). After purification by neutral preparative HPLC, the title compound (32 mg, 51%) was obtained as a light brown solid.

1H-NMR (DMSO-d6, 500MHz): d [ppm] = 12.18 (s, 1H), 9.01 (t, J = 6.1Hz, 1H), 8.14 (s, 1H), 7 .57-7.39 (m, 4H), 7.13 (s, 2H), 4.70 (d, J=6.1Hz, 2H), 3.96 (s, 2H), 3.19 (t. , J=6.8 Hz, 2H), 2.98 (t, J=6.8 Hz, 2H), 2.58 (s, 3H)
HPLCMS (Method B): [m/z]: 408.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-(1H-imidazol-2-ylmethyl)-1,3-thiazole-4-carboxamide (Example Compound No. 95)

In a manner similar to General Procedure 2, 4M HCl in dioxane (1 ml, 4 mmol) was added to tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4- When [(1H-imidazol-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate (64) (61 mg, 0.13 mmol) in dioxane (4 ml) was added at room temperature for 18 hours. After purification by basic preparative HPLC, the title compound (23 mg, 48%) was obtained as a yellow solid.

1H-NMR (DMSO-d6,500MHz): d [ppm] = 12.19 (s, 1H), 11.77 (s, 1H), 8.61 (t, J = 5.9Hz, 1H), 8 .14 (s, 1H), 7.49 (br s, 2H), 7.13 (dd, J=5.9, 2.8 Hz, 2H), 7.00 (br s, 1H), 6.81 (Br s, 1H), 4.48 (d, J=5.9 Hz, 2H), 3.97 (s, 2H), 3.17 (d, J=6.2 Hz, 2H), 2.98( t, J=6.8 Hz, 2H)
HPLCMS (Method B): [m/z]: 382.1 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-{[2-(morpholin-4-yl)pyridin-4-yl]methyl}-1, 3-thiazole-4-carboxamide (Example compound No. 96)

In a similar manner to General Procedure 2, 4M HCl in dioxane (1 ml) was added to tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({ [2-(Morpholin-4-yl)pyridin-4-yl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate (65) (108 mg, 0.19 mmol) in dioxane (4 ml). The solution was added at room temperature for 15 hours to give the title compound (46 mg, 51%) as an orange solid after purification by neutral preparative HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.90 (t, J=6.3 Hz, 1H), 8.15 (s, 1H), 8.03 (d, J=5.0. 1 Hz, 1H), 7.50 (dd, J=5.7, 3.3 Hz, 2H), 7.14 (dq, J=7.1, 3.9 Hz, 2H), 6.73 (s, 1H ), 6.61 (d, J=5.1 Hz, 1H), 4.38 (d, J=6.3 Hz, 2H), 4.15 (d, J=29.7 Hz, 1H), 4.05. (S, 2H), 3.72-3.62 (m, 4H), 3.23 (t, J=6.8Hz, 2H), 3.18 (s, 2H) 3.07 (t, J= 6.8Hz, 2H)
HPLCMS (Method B): [m/z]: 478.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(5-methylpyridin-2-yl)methyl]-1,3-thiazole-4- Carboxamide (Example compound No. 97)

In a manner similar to general procedure 2, 4M HCl in dioxane (0.24 ml, 0.96 mmol) was added to tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2. -(4-{[(5-Methylpyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (66) (48 mg, 0.095 mmol) in dioxane (2 ml) Addition of the solution at room temperature for 12 hours gave the title compound (10 mg, 26%) as a colorless oil after purification by neutral preparative HPLC.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.31 (s, 1H), 8.10 (s, 1H), 7.60 (dd, J=8.0, 1.8Hz, 1H), 7.52 (dd, J=6.0, 3.1 Hz, 2H), 7.29 (d, J=8.0 Hz, 1H), 7.22 (dd, J=6.0, 3) .1 Hz, 2H), 4.65 (s, 2H), 4.10 (s, 2H), 3.28 (t, J=6.6 Hz, 2H), 3.13 (t, J=6.6 Hz) , 2H), 2.33 (s, 3H)
HPLC MS (Method D): [m/z]: 407.1 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-{[6-(dimethylamino)pyridin-3-yl]methyl}-1,3-thiazole -4-carboxamide (Example compound No. 98)

In a manner similar to general procedure 2, 4M HCl in dioxane (0.17 ml, 0.68 mmol) was added to tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2. -[4-({[6-(Dimethylamino)pyridin-3-yl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate (67) (36 mg, 0.07 mmol) in dioxane ( (2 ml) in solution at room temperature for 12 hours to give the title compound (8 mg, 27%) as a colorless oil after purification by neutral preparative HPLC.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.07(s,1H),8.05(d,J=2.1Hz,1H),7.57-7.50(m, 3H), 7.26-7.20 (m, 2H), 6.61 (d, J=8.8Hz, 1H), 4.43 (s, 2H), 4.07 (s, 2H), 3 .24 (t, J=6.6 Hz, 2H), 3.10 (t, J=6.6 Hz, 2H), 3.06 (s, 6H)
HPLCMS (Method B): [m/z]: 436.3 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(2-methylpyridin-4-yl)methyl]-1,3-thiazol-4- Carboxamide (Example compound No. 99)

In a manner similar to general procedure 2, 4M HCl in dioxane (0.18 ml, 0.72 mmol) was added to tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2. -(4-{[(2-Methylpyridin-4-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (68) (36 mg, 0.07 mmol) in dioxane (2 ml). The solution was added at room temperature for 12 hours to give the title compound (20 mg, 69%) as a colorless oil after purification by neutral preparative HPLC.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.31 (d, J=5.3Hz, 1H), 8.11 (s, 1H), 7.52 (dd, J=5. 9, 3.2 Hz, 2H), 7.30-7.13 (m, 4H), 4.58 (s, 2H), 4.09 (s, 2H), 3.28 (t, J=6. 6Hz, 2H), 3.13 (t, J=6.6Hz, 2H), 2.49 (s, 3H)
HPLC MS (method B): [m/z]: 407.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-1,3 -Thiazole-4-carboxamide (Example compound No. 100)

In a manner similar to general procedure 2, 4M HCl in dioxane (0.36 ml, 1.44 mmol) was added to tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2. Of -(4-{[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (69) (74 mg, 0.15 mmol) Addition to a solution in dioxane (2 ml) at room temperature for 12 hours gave the title compound (19 mg, 33%) as a colorless oil after purification by neutral preparative HPLC.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.05(s, 1H), 7.53(dd, J=5.8, 3.2Hz, 2H), 7.38(s, 1H), 7.30-7.17 (m, 2H), 4.38 (s, 2H), 4.07 (s, 2H), 3.74 (s, 3H), 3.23 (t, J). =6.7 Hz, 2H), 3.09 (t, J=6.7 Hz, 2H), 2.29 (s, 3H)
HPLCMS (Method D): [m/z]: 410.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}- 1,3-thiazole-4-carboxamide (Example compound No. 101)

In a similar manner to General Procedure 2 tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[ in MeOH (2.1 ml) at 50° C. for 2 hours. 4-({[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate (70) (216 mg, 0.163 mmol, Purity by basic preparative HPLC with 45% purity) and 12M HCl (2.1 ml) afforded the title compound (67 mg, 80%) as a white solid.

1H-NMR (DMSO-d6,500MHz): d[ppm]=12.18(s, 1H), 8.91-8.86(m, 1H), 8.77(t, J=5.6Hz, 1H), 8.45 (d, J=1.5 Hz, 1H), 8.14 (s, 1H), 7.59-7.35 (m, 2H), 7.19-7.05 (m, 2H), 4.75 (d, J=5.6 Hz, 2H), 3.97 (s, 2H), 3.20 (t, J=6.8 Hz, 2H), 2.99 (t, J= 6.8Hz, 2H)
HPLCMS (Method D): [m/z]: 495.0 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-chloro-5-fluoropyridin-2-yl)methyl]-1,3- Thiazole-4-carboxamide (Example compound No. 102)

In a similar manner to general procedure 2 for 2 hours at 50° C. in tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-( in MeOH (1.6 ml). 4-{[(3-chloro-5-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (71) (157 mg, 76%, purity 62%) and After purification by basic preparative HPLC with 12M HCl (1.6 ml), the title compound (50 mg, 62%) was obtained as a white solid.

1H-NMR (DMSO-d6, 500MHz): d [ppm] = 12.17 (s, 1H), 8.67 (t, J = 5.6Hz, 1H), 8.54 (d, J = 2. 5 Hz, 1 H), 8.14 (s, 1 H), 8.11 (dd, J=8.5, 2.5 Hz, 1 H), 7.60-7.36 (m, 2 H), 7.12 ( d, J=4.7 Hz, 2H), 4.64 (d, J=5.1 Hz, 2H), 3.97 (s, 2H), 3.19 (t, J=6.8 Hz, 2H), 2.98 (t, J=6.8Hz, 2H)
HPLC MS (Method D): [m/z]: 445.1 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(2-fluoropyridin-3-yl)methyl]-1,3-thiazol-4- Carboxamide (Example compound No. 103)

In a similar manner to general procedure 2 for 5 hours at room temperature in tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4 -{[(2-fluoropyridin-3-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (72) (127 mg, 0.249 mmol) and 4M HCl in dioxane (0.622 ml). (2.487 mmol) gave the title compound (26 mg, 25%) as a yellow solid after purification by basic preparative HPLC.

1H-NMR (DMSO-d6, 500MHz): d[ppm]=8.94(t, J=6.2Hz, 1H), 8.17(s, 1H), 8.13-8.09(m, 1H), 7.85-7.79 (m, 1H), 7.55-7.46 (m, 2H), 7.32-7.28 (m, 1H), 7.18-7.12( m, 2H), 4.47 (d, J=6.1 Hz, 2H), 4.11-4.08 (m, 2H), 3.27-3.23 (m, 2H), 3.15-. 3.08 (br m, 2H)
HPLCMS (Method F): [m/z]: 411.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(2-methoxypyridin-4-yl)methyl]-1,3-thiazol-4- Carboxamide (Example compound No. 104)

In a similar manner to General Procedure 2 for 2 hours at 50° C. in tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4- {[(2-Methoxypyridin-4-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (73) (104 mg, 0.199 mmol, purity 96%) and 12M HCl (1 ml). After purification by basic preparative HPLC, the title compound (35 mg, 42%) was obtained as a pale yellow solid.

1H-NMR (DMSO-d6,500MHz): d[ppm]=12.17(s, 1H), 8.95(t, J=6.3Hz, 1H), 8.13(s, 1H), 8 .06 (d, J=5.3 Hz, 1H), 7.58-7.38 (m, 2H), 7.17-7.07 (m, 2H), 6.89 (dd, J=5. 3,1.1 Hz, 1H), 6.65 (s, 1H), 4.40 (d, J=6.3 Hz, 2H), 3.96 (s, 2H), 3.81 (s, 3H) , 3.19 (t, J=6.8 Hz, 2H), 2.98 (t, J=6.8 Hz, 2H)
HPLCMS (Method B): [m/z]: 423.1 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(4,6-dimethylpyridin-3-yl)methyl]-1,3-thiazole- 4-carboxamide (Example compound No. 105)

In a similar manner to General Procedure 2 for 20 h at 45° C. in tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4- {[(4,6-Dimethylpyridin-3-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (74) (0.077 g, 0.148 mmol) and 12M HCl (0. 287 ml, 3.449 mmol) gave the title compound (25 mg, 40%) as a yellow solid after purification by neutral preparative HPLC.

1H-NMR (DMSO-d6,500MHz): d[ppm]=8.73(t, J=6.1Hz, 1H), 8.25(s, 1H), 8.11(s, 1H), 7 .56-7.37 (br m, 2H), 7.16-7.09 (m, 2H), 7.02 (s, 1H), 4.42 (d, J=6.0Hz, 2H), 3.95(s, 2H), 3.16(t, J=6.5Hz, 5H), 2.96(t, J=6.8Hz, 2H), 2.37(s, 3H), 2. 28 (s, 3H)
HPLC MS (Method G): [m/z]: 421.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(4-methylpyridin-2-yl)methyl]-1,3-thiazole-4- Carboxamide (Example compound No. 106)

In a similar manner to General Procedure 2 for 20 h at 45° C. in tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4- {[(4-Methylpyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (75) (90 mg, 0.178 mmol) and 12M HCl (0.345 ml, 4. (143 mmol) gave the title compound (21 mg, 29%) as a yellow solid after purification by neutral preparative HPLC.

1H-NMR (DMSO-d6, 500MHz): d[ppm]=8.82(t, J=6.0Hz, 1H), 8.34(d, J=5.0Hz, 1H), 8.14( s, 1H), 7.57-7.39 (m, 2H), 7.14-7.10 (m, 3H), 7.09 (d, J=5.1Hz, 1H), 4.52( d, J=6.0 Hz, 2H), 3.97 (s, 2H), 3.19 (t, J=6.8 Hz, 3H), 3.01-2.96 (m, 2H), 2. 27 (s, 3H)
HPLC MS (Method G): [m/z]: 407.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole- 4-carboxamide (Example compound No. 108)

In a similar manner to General Procedure 2 for 16 hours at room temperature in tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{ in dioxane (2 ml). [(3,5-Difluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (77) (112 mg, 0.21 mmol) and 4M HCl in dioxane (0.53 ml). , 2.119 mmol) after purification by neutral preparative HPLC to give the title compound (36.7 mg, 40%) as a colorless oil.

1H-NMR (Methanol-d ₄ , 500 MHz): d[ppm]=8.27 (d, J=2.3 Hz, 1H), 8.09 (s, 1H), 7.61-7.55 (m , 1H), 7.54-7.49 (m, 2H), 7.25-7.16 (m, 2H), 4.74 (s, 2H), 4.10 (s, 2H), 3. 28 (t, J=6.6 Hz, 2H), 3.14 (t, J=6.6 Hz, 2H)
HPLCMS (Method B): [m/z]: 429.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-{[3-(hydroxymethyl)pyridin-2-yl]methyl}-1,3-thiazole -4-carboxamide (Example compound No. 110)

In a manner similar to General Procedure 2, 4M HCl in dioxane (3.28 ml, 13.13 mmol) was added to tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2. -(4-{[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (78)( 191.5 mg, 0.09 mmol, purity 30%) in dioxane (2 ml) at room temperature for 15 hours, after purification by basic preparative HPLC the title compound (8.9 mg, 23.5%) is yellow. Obtained as an oil.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.21 (s, 1H), 8.75 (t, J=5.0 Hz, 1H), 8.40 (dd, J=4. 8, 1.4 Hz, 1H), 8.14 (s, 1H), 7.81-7.77 (m, 1H), 7.57-7.40 (br m, 2H), 7.31 (dd , J=7.6, 4.8 Hz, 1H), 7.14-7.10 (m, 2H), 5.41 (br s, 1H), 4.63-4.59 (m, 4H), 3.97(s, 2H), 3.20(t, J=6.8Hz, 2H), 2.98(t, J=6.8Hz, 2H)
HPLCMS (Method B): [m/z]: 422.2 [M+H] ^+.
General scheme 2 above:
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-1,3-thiazole-4-carboxylic acid (80)

In a manner similar to General Procedure 5, LiOH (0.142 g, 5.92 mmol) and tert-butyl 2-({[(tert-butoxy)carbonyl]({2-[ 4-(methoxycarbonyl)-1,3-thiazol-2-yl]ethyl})amino}methyl)-1H-1,3-benzodiazol-1-carboxylate (7) (1.12 g) at room temperature Stir for 16 hours. The reaction mixture was acidified to pH ˜1-2 with saturated KHSO ₄ solution and then concentrated in vacuo. The crude residue was triturated with DCM/IPA followed by MeOH/EtOAc to give the title compound (1.2 g, 50% pure) as a cream solid.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.39 (s, 1H), 7.96-7.91 (m, 2H), 7.71-7.76 (m, 2H). , 5.07 (s, 2H), 3.84 (t, J=6.3Hz, 2H), 3.64 (t, J=6.3Hz, 2H)
HPLCMS (Method A): [m/z]: 303.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-{[2-(morpholin-4-yl)phenyl]methyl}-1,3-thiazole- 4-carboxamide (Example compound No. 63)

In a similar manner to General Procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-1,3-thiazole-4-carboxylic acid in DMF (5 ml). Acid (80) (200 mg, 0.66 mmol, purity 50%), 1-[2-(morpholin-4-yl)phenyl]methanamine (127 mg, 0.66 mmol), DIPEA (0.35 ml, 1.98 mmol) and After purification by basic preparative HPLC with HATU (377 mg, 0.99 mmol), the title compound (37 mg, 12%) was obtained as a yellow solid.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.06(s, 1H), 7.50(dd, J=5.9, 3.2Hz, 2H), 7.27(t, J=8.0 Hz, 2 H), 7.24-7.18 (m, 2 H), 7.16 (d, J=7.6 Hz, 1 H), 7.06 (t, J=7.6 Hz, 1 H). ), 4.67 (s, 2H), 4.05 (s, 2H), 3.88-3.80 (m, 4H), 3.23 (t, J=6.8Hz, 2H), 3. 07 (t, J=6.8 Hz, 2H), 2.90-2.84 (m, 4H)
HPLCMS (Method B): [m/z]: 477.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(1-methyl-1H-imidazol-2-yl)methyl]-1,3-thiazole -4-carboxamide (Example compound No. 64)

In a manner similar to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-1,3-in DCM (5 ml) and DMF (1 ml). Thiazol-4-carboxylic acid (80) (200 mg, 0.33 mmol, purity 50%), 1-(1-methyl-1H-imidazol-2-yl)methanamine (36 mg, 0.33 mmol), DIPEA (230 μl, 1 .32 mmol) and HATU (189 mg, 0.496 mmol) gave the title compound (15 mg, 12%) after purification by basic preparative HPLC.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.09 (s, 1H), 7.53 (dd, J=5.9, 3.2Hz, 2H), 7.26-7. 20 (m, 2H), 7.03 (d, J = 1.1Hz, 1H), 6.89 (d, J = 1.2Hz, 1H), 4.66 (s, 2H), 4.08 ( s, 2H), 3.73 (s, 3H), 3.25 (t, J=6.7 Hz, 2H), 3.11 (t, J=6.7 Hz, 2H)
HPLCMS (Method B): [m/z]: 396.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(2-fluorophenyl)methyl]-1,3-thiazole-4-carboxamide (Example Compound 65)

In a manner similar to general procedure 6, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-1,3-thiazole-4-carboxylic acid in DMF (2 ml). Acid (80) (200 mg, 0.53 mmol, 50% purity), 1-(2-fluorophenyl)methanamine (66 mg, 0.53 mmol), DIPEA (369 μl, 2.12 mmol) and HATU (302 mg, 0.79 mmol). After purification by basic preparative HPLC, the title compound (13 mg, 6%) was obtained as a white solid.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.09 (s, 1H), 7.53 (dd, J=5.9, 3.2Hz, 2H), 7.40-7. 35 (m, 1H), 7.32-7.26 (m, 1H), 7.25-7.19 (m, 2H), 7.15-7.05 (m, 2H), 4.64 ( s, 2H), 4.08 (s, 2H), 3.26 (t, J=6.7Hz, 2H), 3.11 (t, J=6.7Hz, 2H)
HPLCMS (Method D): [m/z]: 410.2 [M+H] ^+.
General Scheme 4 above:
2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylic acid (87)

In a similar manner to General Procedure 5, ethyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole- in THF/water (200 ml/70 ml) for 20 hours at room temperature. 4-Carboxylate (1) (8 g, 26.63 mmol) and LiOH (1.91 g, 79.90 mmol) gave the title compound (10.16 g, 99.7%) as a yellow oil.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.32 (s, 1H), 6.99 (s, 1H), 3.28 (t, J=6.9 Hz, 2H is a solvent. Duplication), 3.10 (t, J=6.9 Hz, 2H), 1.36 (s, 9H)
1H-NMR (Methanol-d4,500MHz): d[ppm]=8.24 (s, 1H), 3.46 (t, J=6.6Hz, 2H), 3.19 (t, J=6. 6Hz, 2H), 1.41 (s, 9H)
HPLC MS (Method A): [m/z]: 294.9 [M+H] ^+.
2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-1,3-thiazole-4-carboxylic acid (88)

In a manner similar to General Procedure 5, methyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-1,3-thiazole-4 in THF/water (20 ml/20 ml). -Carboxylate (3) (769 mg, 2.56 mmol) and LiOH (310 mg, 13 mmol) gave the title compound (681 mg, 88%) as a yellow oil.

1H-NMR (DMSO-d6, 250MHz): d[ppm]=12.76(s, 1H), 6.99(t, J=5.6Hz, 1H), 3.30-3.19(m, 2H), 3.01 (t, J=6.9 Hz, 2H), 2.65 (s, 3H), 1.37 (s, 9H)
HPLCMS (Method A): [m/z]: 301.05 [M+H] ^+.
2-(3-{[(tert-butoxy)carbonyl]amino}propyl)-1,3-thiazole-4-carboxylic acid (89)

In a manner similar to general procedure 5, ethyl 2-(3-{[(tert-butoxy)carbonyl]amino}propyl)-1,3-thiazole-4-carboxylate in THF (12 ml) and water (4 ml). (4) (726 mg, 2.31 mmol) and LiOH (166 mg, 6.93 mmol) gave the crude title compound (791 mg) as a yellow oil.

1H-NMR (DMSO-d6, 500MHz): d[ppm]=8.13(s, 1H), 6.91(t, J=5.0Hz, 1H), 3.05-2.93(m, 4H), 1.83 (p, J=7.2Hz, 2H), 1.38 (s, 9H)
HPLCMS (Method A): [m/z]: 285 [M+H] ^+.
tert-Butyl N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (90)

In a manner similar to general procedure 6, (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (8.03 g, 40.35 mmol), 2-( in THF (300 ml) at room temperature for 2 hours. 2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylic acid (87) (10.2 g, 26.9 mmol), DIPEA (28.1 ml, 161.4 mmol) and After purification by HATU (12.3 g, 32.3 mmol) by flash column chromatography (eluting with a gradient of 20-100% EtOAc/heptane), the title compound (13.27 g) was obtained as an orange oil.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.70 (t, J=5.6 Hz, 1H), 8.39 (d, J=4.6 Hz, 1H), 8.15( s, 1H), 7.73 to 7.67 (m, 1H), 7.40 (dt, J=8.5, 4.4 Hz, 1H), 7.04 (s, 1H), 4.65 ( d, J=5.6 Hz, 2H), 3.31 (t, J=6.8 Hz, 2H, overlapping with NMR solvent), 3.13 (t, J=6.8 Hz, 2H), 1.36( s, 9H)
HPLCMS (Method A): [m/z]: 381 [M+H] ^+.
tert-Butyl N-{2-[4-(benzylcarbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate (91)

In a similar manner to general procedure 6, 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylic acid (87) (4. 09 g, 15.0 mmol), benzylamine (1.8 ml, 16.5 mmol), DIPEA (7.9 ml, 45.1 mmol) and HATU (8.570 g, 22.5 mmol) by flash column chromatography (20-100). After purification by elution with a gradient of EtOAc/heptane (%), the title compound (3.38 g, 56%, 90% pure) was obtained as a yellow oil.

_{1H-NMR (CDCl 3, 500MHz} ): d [ppm] = 8.03 (s, 1H), 7.61 (s, 1H), 7.39-7.32 (m, 4H), 7.31- 7.27 (m, 1H), 4.64 (d, J=6.1 Hz, 2H), 3.54 (d, J=6.4 Hz, 2H), 3.17 (t, J=6.4 Hz) , 2H), 1.42 (s, 9H)
HPLC MS (Method E): [m/z]: 384 [M+Na] ^+.
tert-Butyl N-(2-{4-[(pyridin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate (92)

In a similar manner to General Procedure 6, 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylic acid (87) (0. 500 g, 1.836 mmol), 1-(pyridin-2-yl)methanamine (0.199 g, 1.836 mmol), HATU (1.047 g, 2.754 mmol) and DIPEA (0.959 ml, 5.508 mmol) and by After purification by flash chromatography (using a gradient of 20% heptane: 80% ethyl acetate to 100% ethyl acetate), the title compound (0.905 g, quantitative) was obtained as a yellow oil.

HPLCMS (Method A): [m/z]: 363.05 [M+H] ^+.
tert-Butyl N-(2-{4-[(pyridazin-3-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate (93)

In a similar manner to General Procedure 6, 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylic acid (87) (0. Flash column chromatography with 7 g, 2.57 mmol), pyridazin-3-ylmethanamine (0.42 g, 3.86 mmol), DIPEA (2.24 ml, 12.85 mmol) and HATU (1.47 g, 3.86 mmol). After purification by chromatography (eluting with a gradient of 0-5% MeOH-DCM), the title compound (0.919 g, 98%) was obtained as a brown oil.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=9.21 (d, J=4.0 Hz, 1H), 8.41-8.32 (br m, 1H), 8.03 (s, 1H), 7.91-7.85 (br m, 1H), 7.77-7.69 (br m, 1H), 5.01 (d, J=5.7 Hz, 2H), 4.96 ( br s, 1H), 3.65-3.46 (m, 2H), 3.20 (t, J=6.2Hz, 2H), 1.42 (s, 9H).
HPLC MS (Method A): [m/z]: 364.05 [M+H] ^+.
tert-Butyl N-[2-(4-{[(6-methylpyridazin-3-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (94)

In a similar manner using general procedure 6 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylic in THF (35 ml) and DMF (5 ml). Acid (87) (1.3 g, 4.15 mmol), (6-methylpyridazin-3-yl)methanamine hydrochloride (0.8 g, 5.01 mmol), DIPEA (2.89 ml, 16.61 mmol) and HATU ( 1.90 g, 5.01 mmol) flash column chromatography (kp-NH, eluting with a gradient of 0-15% MeOH/EtOAc) followed by a second flash column chromatography (kp-NH, 70-100%). After purification by elution with an EtOAc/heptane gradient) the title compound (0.878 g, 45%) was obtained as a colorless oil.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=9.04 (t, J=6.0 Hz, 1H), 8.17 (s, 1H), 7.50 (q, J=8. 6 Hz, 2 H), 7.05 (s, 1 H), 4.71 (d, J=6.1 Hz, 2 H), 3.13 (t, J=6.8 Hz, 2 H), 2.59 (s, 3H), 1.36 (s, 9H)
HPLC MS (Method A): [m/z]: 378.05 [M+H] ^+.
tert-Butyl N-(2-{4-[(pyrimidin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate (95)

In a similar manner to General Procedure 6, 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylic acid (87) (0. 7 g, 2.57 mmol), pyrimidin-2-ylmethanamine (0.42 g, 3.86 mmol), DIPEA (2.24 ml, 12.85 mmol) and HATU (1.47 g, 3.86 mmol) by flash column chromatography. After purification by chromatography (eluting with a gradient of 0-5% MeOH-DCM), the title compound (0.545 g, 58%) was obtained as a pale yellow solid.

1H-NMR (CDCl ₃ , 250 MHz): d [ppm] = 8.83 (s, 1H), 8.81 (s, 1H), 8.46 (br s, 1H), 8.06 (s, 1H). ), 7.32 (app t, J=4.8 Hz, 1H), 5.01 (br s, 1H), 4.97 (d, J=5.3 Hz, 2H), 3.67-3.56. (M, 2H), 3.26 (t, J
=6.4 Hz, 2H), 1.47 (s, 9H)
HPLC MS (Method A): [m/z]: 364.05 [M+H] ^+.
tert-Butyl N-[2-(4-{[(5-methylpyrimidin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (96)

In a similar manner to general procedure 6, 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylic acid (in THF (15 ml) and DMF (3 ml) ( 87) (500 mg, 1.6 mmol, purity 87%), (5-methylpyrimidin-2-yl)methanamine (295 mg, 2.4 mmol), DIPEA (1.39 ml, 7.99 mmol) and HATU (911 mg, 2. 4 mmol) afforded the crude title compound (600 mg, 85%, 85% pure) as a yellow oil after flash chromatography (eluting with a gradient of 0-80% EtOAc/heptane).

HPLC MS (Method A): [m/z]: 378.10 [M+H] ^+.
tert-Butyl N-{2-[4-({5H,6H,7H-cyclopenta[b]pyridin-7-yl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate (97)

In a similar manner to General Procedure 6, 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylic acid (87) (1. 2 g, 4.41 mmol), 5H,6H,7H-cyclopenta[b]pyridin-7-amine hydrochloride (1.13 g, 6.61 mmol), DIPEA (2.3 ml, 13.22 mmol) and HATU (2.51 g). , 6.61 mmol) after purification by flash column chromatography (eluting with a gradient of 0-5% MeOH/DCM) to give the title compound (1.53 g, 85%) as a pale pink powder.

HPLCMS (Method A): [m/z]: 389.15 [M+H] ^+.
tert-Butyl N-[2-(4-{[(3-methoxypyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (98)

In a similar manner to General Procedure 6 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylic acid (87) (250) in DCM (15 ml). 0.918 mmol), (3-methoxypyridin-2-yl)methanamine dihydrochloride (213 mg, 1.01 mmol), DIPEA (0.80 ml, 4.59 mmol) and HATU (524 mg, 1.38 mmol) with flash column. After chromatography (eluting with a gradient of 30-100% EtOAc/heptane) the crude title compound (417 mg) was obtained as a yellow oil.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.68 (s, 1H), 8.21 (d, J=4.7 Hz, 1H), 8.02 (s, 1H), 7. 21 (dd, J=8.2, 4.7 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 5.02 (s, 1H), 4.76 (d, J=4) 0.7 Hz, 2H), 3.89 (s, 3H), 3.63 (d, J=6.0 Hz, 2H), 3.23 (t, J=6.0 Hz, 2H), 1.44 (s , 9H)
HPLC MS (Method A): [m/z]: 393.40 [M+H] ^+.
tert-Butyl N-[2-(4-{[(3-methoxypyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (99)

In a similar manner to General Procedure 6 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylic acid (87) (250) in DCM (15 ml). 0.918 mmol), 1-(1H-benzimidazol-2-yl)methanamine (149 mg, 1.01 mmol), DIPEA (0.48 ml, 2.75 mmol) and HATU (524 mg, 1.38 mmol) by flash column chromatography. After purification by chromatography (eluting with a gradient of 0-10% MeOH/DCM), the crude title compound (0.709 mg, quantitative, 81% pure) was obtained as a yellow oil.

HPLCMS (Method A): [m/z]: 402 [M+H] ^+.
tert-Butyl N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-5-methyl-1,3-thiazol-2-yl)ethyl]carbamate (100)

In a manner similar to general procedure 6, 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-1,3-thiazole-4-carboxylic acid (88) in DCM (30 ml). ) (680 mg, 2.37 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (615 mg, 3.09 mmol), TEA (1.16 ml, 8.0 mmol) and HATU (1350 mg, 3). .56 mmol) gave the title compound (824 mg, 85%) as a yellow oil.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.45 (m, 2H), 7.42 (ddd, J=9.4, 8.3, 1.2 Hz, 1H), 7.30. -7.24 (m, 1H), 4.99 (s, 1H), 4.83 (dd, J=5.2, 1.5Hz, 2H), 3.59 (d, J=6.0Hz, 2H), 3.13 (t, J=6.0 Hz, 2H), 2.83 (s, 3H), 1.46 (s, 9H)
HPLC MS (Method A): [m/z]: 395.15 [M+H] ^+.
tert-Butyl N-(2-{5-methyl-4-[(pyrimidin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate (101)

In a similar manner to General Procedure 6, 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-1,3-thiazole-4-carboxylic acid (88) (0.315 g , 0.912 mmol), 1-(pyrimidin-2-yl)methanamine (0.119 g, 1.094 mmol), THF (7 ml), DMF (1 ml), DIPEA (0.318 ml, 1.824 mmol) and HATU (0. .416 g, 1.094 mmol) after purification by flash column chromatography (using a gradient of 30-100% EtOAc in heptane) to afford the title compound (0.134 g, 27%) as a colorless oil.

HPLC MS (Method A): [m/z]: 378.10 [M+H] ^+.
tert-Butyl N-[3-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)propyl]carbamate (102)

In a manner similar to general procedure 6, 2-(3-{[(tert-butoxy)carbonyl]amino}propyl)-1,3-thiazole-4-carboxylic acid (in DMF (4 ml) and THF (4 ml) ( 89) (661 mg, 2.31 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (689 mg, 3.46 mmol), DIPEA (2.41 ml, 13.85 mmol) and HATU (1053 mg, 2.77 mmol) afforded the title compound (914 mg, 93%, 93% pure) as a yellow oil after purification by flash chromatography (eluting with a gradient of 20-100% EtOAc/heptane).

HPLCMS (Method A): [m/z]: 395.05 [M+H] ⁺
2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide dihydrochloride (103)

In a manner similar to General Procedure 2 12M HCl in MeOH (250 ml) (35.3 ml) and tert-butyl N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}. -1,3-Thiazol-2-yl)ethyl]carbamate (90) (13.3 g, 28.25 mmol) was stirred at 50°C for 3 hours. The mixture was concentrated in vacuo to give the title compound (12.8g) as an off-white solid.

1H-NMR (DMSO-d6,500MHz): d[ppm]=8.98 (s, 1H), 8.39 (d, J=4.7Hz, 1H), 8.21 (s, 1H), 8 .17 (s, 3H), 7.72 (t, J=9.3 Hz, 1H), 7.42 (dt, J=8.5, 4.4 Hz, 1H), 4.67 (d, J= 5.8 Hz, 2H), 3.38 (t, J=6.5 Hz, 2H), 3.30-3.25 (m, 2H)
HPLCMS (Method A): [m/z]: 280.9 [M+H] ^+.
2-(2-Aminoethyl)-N-benzyl-1,3-thiazole-4-carboxamide hydrochloride (104)

In a similar manner to general procedure 2 for 4 hours at room temperature 12M HCl (2.5 ml) in MeOH (4.5 ml) and tert-butyl N-{2-[4-(benzylcarbamoyl)-1,3-. Thiazol-2-yl]ethyl}carbamate (91) (456 mg, 1.29 mmol) afforded the title compound (336 mg, 100%) as a beige solid. The product was used in subsequent reactions without purification.

HPLC MS (Method E): [m/z]: 261.95 [M+H] ^+.
2-(2-Aminoethyl)-N-(pyridin-2-ylmethyl)-1,3-thiazole-4-carboxamide dihydrochloride (105)

In a manner similar to general procedure 2, tert-butyl N-(2-{4-[(pyridin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate in MeOH (9 ml). (92) (0.905g, 2.50mmol), 12M HCl (4.852ml, 58.23mmol) gave the title compound (0.840g, quantitative) as a white solid.

HPLCMS (Method A): [m/z]: 262.95 [M+H] ^+.
2-(2-Aminoethyl)-N-(pyridazin-3-ylmethyl)-1,3-thiazole-4-carboxamide dihydrochloride (106)

In a similar manner to general procedure 2 for 16 hours at room temperature in tert-butyl N-(2-{4-[(pyridazin-3-ylmethyl)carbamoyl]-1,3-thiazol-2- in MeOH (15 ml). Il}ethyl)carbamate (93) (0.919 g, 2.53 mmol) and 12M HCl (4.22 ml) gave the title compound (0.840 g, 97%) as a brown residue.

1H-NMR (heavy water, 500 MHz): d[ppm]=9.17 (dd, J=4.9, 1.5 Hz, 1H), 8.12 (s, 1H), 8.03 (dd, J=). 8.6, 1.5 Hz, 1H), 7.99 (dd, J=8.6, 4.9 Hz, 1H), 4.86 (s, 2H), 3.45 to 3.39 (m, 2H) ) 3.48 to 3.43 (m, 2H)
HPLC MS (Method A): [m/z]: 263.95 [M+H] ^+.
2-(2-Aminoethyl)-N-[(6-methylpyridazin-3-yl)methyl]-1,3-thiazole-4-carboxamide dihydrochloride (107)

In a similar manner to General Procedure 2 for 24 hours at room temperature in tert-butyl N-[2-(4-{[(6-methylpyridazin-3-yl)methyl]carbamoyl}-1, MeOH (15 ml). 3-Thiazol-2-yl)ethyl]carbamate (94) (878 mg, 1.86 mmol) and 12M HCl (3.10 ml) gave the title compound (764 mg, quantitative) as an off-white solid. The product was used in subsequent reactions without purification.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.49 (d, J=8.9 Hz, 1H), 8.41 (d, J=8.9 Hz, 1H), 8.26 (s, 1H), 4.97 (s, 2H), 3.53-3.47 (m, 4H), 2.91 (s, 3H).
HPLC MS (Method A): [m/z]: 277.95 [M+H] ^+.
2-(2-Aminoethyl)-N-(pyrimidin-2-ylmethyl)-1,3-thiazole-4-carboxamide dihydrochloride (108)

In a similar manner to general procedure 2 for 16 h at room temperature in tert-butyl N-(2-{4-[(pyrimidin-2-ylmethyl)carbamoyl]-1,3-thiazol-2- in MeOH (15 ml). Il}ethyl)carbamate (95) (0.545 g, 1.499 mmol) and 12M HCl (4.22 ml) gave the title compound (0.530 g, quantitative) as a pale yellow foam.

1H-NMR (heavy water, 500 MHz): d[ppm]=8.73 (d, J=5.1 Hz, 2H), 8.16 (s, 1H), 7.47 (app t, J=5.1 Hz). 1H), 4.80 (s, 2H), 3.51 to 3.46 (m, 2H), 3.45 to 3.41 (m, 2H).
HPLC MS (ESI+): [m/z]: 263.95 [M+H] ⁺ as free base (METCR1673 Genetic 2 min).
2-(2-Aminoethyl)-N-[(5-methylpyrimidin-2-yl)methyl]-1,3-thiazole-4-carboxamide (109)

In a manner similar to general procedure 2, tert-butyl N-[2-(4-{[(5-methylpyrimidin-2-yl)methyl]carbamoyl}-1,3-thiazole-2 in MeOH (10 ml). After purification by flash chromatography (eluting with a gradient of 0-10% 7M ammonia in MeOH/DCM) by -yl)ethyl]carbamate (96) (600 mg, 1.59 mmol) and 12M HCl (2.65 ml). The compound free base (283 mg, 44%) was obtained as a white solid.

1H-NMR (DMSO-d6,500MHz): d[ppm]=8.77-8.70 (m, 1H), 8.62 (s, 2H), 8.14 (s, 1H), 4.64. (D, J=4.0 Hz, 2H), 3.13 (t, J=6.6 Hz, 2H), 3.02 (t, J=6.6 Hz, 2H), 2.26 (s, 3H) )
HPLC MS (Method A): [m/z]: 278.2 [M+H] ^+.
2-(2-aminoethyl)-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl}-1,3-thiazol-4-carboxamide dihydrochloride (110)

In a manner similar to General Procedure 2, 4M HCl in dioxane (14.45 ml, 57.8 mmol) was added to tert-butyl N-{2-[4-({5H,6H,7H-cyclopenta[b]pyridine- 7-yl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate (97) (1.53 g, 3.94 mmol) was added to an ice-cold solution in MeOH (5 ml). The mixture was stirred at room temperature for 2 hours. The title compound (1.32 g, 93%) _was isolated by filtration after precipitation from Et 2 O (5ml).

HPLC MS (Method A): [m/z]: 289.05 [M+H] ^+.
2-(2-Aminoethyl)-N-[(3-methoxypyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide (111)

In a similar manner to general procedure 2 for 12 hours at room temperature, 12M HCl (2.5 ml) in MeOH (5 ml) and crude tert-butyl N-[2-(4-{[(3-methoxypyridine-2- Il)methyl]carbamoyl}-1,3-thiazol-2-yl-)ethyl]carbamate (98) (417 mg) by flash column chromatography (kp-NH, eluting with a gradient of 0-10% MeOH/DCM). After purification by, the title compound (125 mg) was obtained as a white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.59 (s, 1H), 8.15-8.11 (m, 2H), 7.44 (d, J=8.3 Hz, 1H), 7.33 (dd, J=8.3, 4.7 Hz, 1H), 4.57 (d, J=5.2 Hz, 2H), 3.88 (s, 3H), 3.08 ( t, J=6.6 Hz, 2H), 2.94 (t, J=6.6 Hz, 2H), 2.69 (s, 2H)
HPLC MS (Method A): [m/z]: 292.95 [M+H] ^+.
2-(2-Aminoethyl)-N-(1H-1,3-benzodiazol-2-ylmethyl)-1,3-thiazole-4-carboxamide (112)

In a similar manner to general procedure 2 for 12 hours at room temperature 12M HCl (2.5 ml) in MeOH (5 ml) and crude tert-butyl N-(2-{4-[(1H-1,3-benzodiene. Azol-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate (99) (709 mg, 1.43 mmol, 81% purity) by flash column chromatography (kp-NH, 0-10). After purification by elution with a gradient of% MeOH/DCM), the title compound (111 mg, 25%) was obtained as a brown solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.88 (s, 1H), 8.17 (s, 1H), 7.49 (s, 2H), 7.13 (dd, J). = 6.0, 3.1 Hz, 2H), 4.68 (d, J = 6.0 Hz, 2H), 3.08 (t, J = 6.6 Hz, 2H), 2.95 (t, J = 6.6Hz, 2H)
HPLCMS (Method A): [m/z]: 301.95 [M+H] ^+.
2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-methyl-1,3-thiazol-4-carboxamide dihydrochloride (113)

In a manner similar to general procedure 2, tert-butyl N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-5-methyl-1,3 in MeOH (30 ml). -Thiazol-2-yl)ethyl]carbamate (100) (823 mg, 2.09 mmol) and 12M HCl (3 ml) gave the title compound (794 mg, quantitative) as a tan solid.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.87 (t, J=5.9 Hz, 1H), 8.40 (dt, J=4.4, 1.3 Hz, 1H), 8.13 (s, 3H), 7.73 (ddd, J=9.9, 8.3, 1.2Hz, 1H), 7.43 (dt, J=8.5, 4.5Hz, 1H) , 4.69-4.60 (m, 2H), 3.32-3.19 (m, 4H), 2.71 (s, 3H)
HPLCMS (Method A): [m/z]: 295.05 [M+H] ^+.
2-(2-Aminoethyl)-5-methyl-N-(pyrimidin-2-ylmethyl)-1,3-thiazole-4-carboxamide dihydrochloride (114)

In a similar manner to General Procedure 2, tert-butyl N-(2-{5-methyl-4-[(pyrimidin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate ( 101) (0.482g, 0.795mmol), MeOH (6ml) and 12M HCl (1.325ml, 15.90mmol) gave the title compound (0.420g, 99%) as a yellow solid.

HPLC MS (Method A): [m/z]: 277.95 [M+H] ^+.
2-(3-Aminopropyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide dihydrochloride (115)

In a similar manner to General Procedure 2 4M HCl in dioxane (2.89 ml, 11.55 mol) in dioxane (6 ml) and MeOH (2 ml) and tert-butyl N-[3-(4-{[(3- Fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)propyl]carbamate (102) (0.91 g, 2.31 mmol) gave the title compound (1.13 g, 85%, purity). 64%) was obtained as a pale orange oil. The compound was used in the next step without purification.

HPLCMS (Method A): [m/z]: 295.00 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-methoxypyridin-2-yl)methyl]-1,3-thiazole-4- Carboxamide (Example compound No. 59)

In a similar manner using general procedure 3 for 2 hours at room temperature 2-(2-aminoethyl)-N-[(3-methoxypyridin-2-yl)methyl]-1,3 in DCE (9 ml). Add thiazole-4-carboxamide (111) (90 mg, 0.308 mmol) and 1H-benzimidazole-2-carbaldehyde (49 mg, 0.339 mmol), followed by NaBH(OAc) ₃ (91 mg, 0.431 mmol). After purification by basic preparative HPLC, the title compound (50 mg, 38%) was obtained as a yellow solid.

1H-NMR (DMSO-d6, 500MHz): d [ppm] = 12.18 (s, 1H), 8.58 (t, J = 5.2Hz, 1H), 8.14 (s, 1H), 8 0.09-8.06 (m, 1H), 7.59-7.40 (m, 3H), 7.31 (dd, J=8.3, 4.7 Hz, 1H), 7.12 (d, J=3.5 Hz, 2H), 4.56 (d, J=5.2 Hz, 2H), 3.97 (s, 2H), 3.87 (s, 3H), 3.20 (t, J= 6.8Hz, 2H), 2.98 (t, J=6.8Hz, 2H)
HPLCMS (Method B): [m/z]: 423.2 [M+H] ^+.
N-(1H-1,3-benzodiazol-2-ylmethyl)-2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-1,3-thiazole- 4-carboxamide (Example compound No. 60)

2-(2-Aminoethyl)-N-(1H-1,3-benzodiazol-2-ylmethyl)-1 in DCE (12 ml) in the same manner using general procedure 3 for 2 hours at room temperature. , 3-thiazole-4-carboxamide (112) (111 mg, 0.368 mmol) and 1H-benzimidazole-2-carbaldehyde (59 mg, 0.405 mmol) followed by NaBH(OAc) ₃ (109 mg, 0.516 mmol). After purification by basic preparative HPLC, the title compound (15 mg, 9%) was obtained as a yellow solid.

1H-NMR (DMSO-d6,500MHz): d[ppm]=12.23(s, 2H), 8.89(t, J=5.9Hz, 1H), 8.18(s, 1H), 7 .49 (s, 4H), 7.13 (tt, J=7.0, 3.5Hz, 4H), 4.69 (d, J=5.9Hz, 2H), 3.98 (s, 2H) , 3.21 (t, J=6.8 Hz, 2H), 3.00 (t, J=6.8 Hz, 2H)
HPLCMS (Method B): [m/z]: 430.3 [MH] ^+.
2-(2-{[(6-Fluoro-1H-1,3-benzodiazol-2-yl)methyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1 , 3-thiazole-4-carboxamide trihydrochloride (Example compound No. 114)

2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole in MeOH (10 ml) for 24 hours at room temperature in a manner similar to general procedure 3. -4-Carboxamide dihydrochloride (103) (200 mg, 0.49 mmol), 6-Fluoro-1H-benzimidazole-2-carbaldehyde (89 mg, 0.539 mmol), and DIPEA (0.342 ml, 1.961 mmol). After purification by basic basic preparative HPLC by subsequent addition of NaBH ₄ (28 mg, 0.735 mmol), the title compound (83 mg, free base) was obtained as a brown solid. Stirring of the free base and 12M HCl (1 ml) in MeOH (4 ml) at room temperature gave the title compound (111 mg, 42%) after evaporation of the solvent in vacuo.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.52(s,1H),8.28(s,1H),8.24(s,1H),7.86(s,1H) ), 7.78 (s, 1H), 7.53 (s, 1H), 7.34 (s, 1H), 4.97 (s, 2H), 4.92 (s, 2H), 3.84. (S, 2H), 3.64 (t, J=6.1Hz, 2H)
HPLCMS (Method D): [m/z]: 429.1 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-5-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4- Carboxamide (Example compound 139)

In a similar manner to General Procedure 3, 2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole in MeOH (10 ml) at room temperature for 18 hours. -4-Carboxamide dihydrochloride (103) (400 mg, 0.64 mmol, purity 56%), 1H-1,3-benzodiazole-5-carbaldehyde (112 mg, 0.77 mmol) and DIPEA (0.56 ml, 3.19 mmol), followed NaBH ₄ in (36 mg, by adding 0.96 mmol), after purification by flash column chromatography (KP-NH, elution with a gradient of 0~20% MeOH / DCM), the title compound ( 207 mg, 75.9%) was obtained as a cream solid.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.31-8.29 (m, 1H), 8.14 (s, 1H), 8.10 (s, 1H), 7.64 −7.53 (m, 3H), 7.37−7.33 (m, 1H), 7.29 (dd, J=8.3, 1.3 Hz, 1H), 4.79 (d, J= 1.6Hz, 2H), 3.96(s, 2H), 3.28(t, J=6.9Hz, 2H), 3.09(t, J=6.9Hz, 2H)
HPLCMS (Method C): [m/z]: 411.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-4-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazol-4- Carboxamide (Example compound No. 140)

In a similar manner using general procedure 3 for 18 hours at room temperature 2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3 in MeOH (10 ml). -Thiazole-4-carboxamide dihydrochloride (103) (400 mg, 0.64 mmol, purity 56.3%), 1H-1,3-benzodiazol-4-carbaldehyde (112 mg, 0.77 mmol) and DIPEA ( After purification by flash column chromatography (KP-NH, eluting with a gradient of 0-10% MeOH/DCM) by adding 0.56 ml, 3.19 mmol) followed by NaBH ₄ (36 mg, 0.96 mmol). , The title compound (255 mg, 96.4%) was obtained as an off-white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.41 (s, 1H), 8.65 (t, J=5.5 Hz, 1H), 8.39-8.36 (m, 1H), 8.17 (br s, 1H), 8.12 (br s, 1H), 7.72-7.67 (m, 1H), 7.43-7.37 (m, 1H), 7 .22-7.08 (m, 2H), 4.66 (dd, J=5.7, 1.4 Hz, 2H), 4.13 (s, 1H), 4.04 (s, 1H), 3 .18 (t, J=6.5 Hz, 2H), 2.97-2.87 (m, 2H)
HPLCMS (Method C): [m/z]: 411.2 [M+H] ^+.
2-{3-[(1H-1,3-benzodiazol-2-ylmethyl)amino]propyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4- Carboxamide trihydrochloride (Example compound No. 134)

In a manner similar to general procedure 3, 2-(3-aminopropyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole in MeOH (2 ml) for 16 hours at room temperature. -4-carboxamide dihydrochloride (115) (150 mg, 0.261 mmol, purity 64%), 1H-benzimidazole-2-carbaldehyde (46 mg, 0.314 mmol), DIPEA (0.18 ml, 1.05 mmol), The free base compound (53 mg, 48%) was obtained as a colorless oil after purification by basic preparative HPLC by subsequent addition of NaBH ₄ (15 mg, 0.39 mmol).

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=12.16 (s, 1H), 8.66 (t, J=5.5 Hz, 1H), 8.38 (dt, J=4. 7, 1.4 Hz, 1 H), 8.13 (s, 1 H), 7.70 (ddd, J=10.0, 8.4, 1.2 Hz, 1 H), 7.61-7.27 (m , 2H), 7.11 (dd, J=6.0, 3.1 Hz, 2H), 4.65 (dd, J=5.5, 1.4 Hz, 2H), 3.91 (s, 2H). , 3.09 (t, 2H), 2.64 (t, J=6.8Hz, 2H), 1.92 (m, 2H)
HPLC MS (Method D): [m/z]: 425.2 [M+H] ^+.
The free base (35 mg, 0.082 mmol) and 12M HCl (20 μL, 0.247 mmol) were stirred in MeOH (2 ml) at room temperature and the title compound (44 mg, quantitative) was white after removing the solvent in vacuo. Obtained as a solid.

1H-NMR (D ₂ O, 500 MHz): d[ppm]=8.50 (dd, J=5.4, 1.2 Hz, 1H), 8.19-8.12 (m, 2H), 7. 89-7.78 (m, 3H), 7.66 (dt, J = 6.3, 3.3Hz, 2H), 4.89 (s, 2H), 4.85 (d, J = 1.3Hz). , 2H), 3.46-3.39 (m, 2H), 3.26 (t, J=7.2Hz, 2H), 2.33 (m, 2H).
HPLC MS (Method D): [m/z]: 425.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-5-methyl-1,3- Thiazole-4-carboxamide (Example compound No. 164)

In a similar manner using general procedure 3 for 20 hours at room temperature 2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl in MeOH (10 ml) and DCM (10 ml). ]-5-Methyl-1,3-thiazole-4-carboxamide dihydrochloride (113) (274 mg, 0.75 mmol), 1H-1,3-benzodiazole-2-carbaldehyde (109 mg, 0.75 mmol) , DIPEA (0.45 ml, 2.61 mmol) and anhydrous MgSO ₄ (200 mg), followed by NaBH ₄ (60 mg, 1.48 mmol), followed by purification by preparative HPLC to give the title compound (140 mg, 44%). ) Was obtained as a pale yellow solid.

1H-NMR (DMSO-d6,500MHz): d[ppm]=12.17(s, 1H), 8.59(t, J=5.6Hz, 1H), 8.36(dt, J=4. 7, 1.4 Hz, 1H), 7.70 (ddd, J=9.9, 8.4, 1.1 Hz, 1H), 7.53 (d, J=7.5 Hz, 1H), 7.44 (D, J=7.5 Hz, 1H), 7.40 (dt, J=8.5, 4.4 Hz, 1H), 7.13 (p, J=6.6 Hz, 2H), 4.65− 4.59 (m, 2H), 3.96 (s, 2H), 3.10 (t, J = 6.8Hz, 2H), 2.94 (t, J = 6.8Hz, 2H), 2. 68 (s, 3H)
HPLCMS (Method C): [m/z]: 425.2 [M+H] ^+.
General Procedure 7: 2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl ]-1,3-thiazole-4-carboxamide (Example compound No. 94)

2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide dihydrochloride (103) (2.0 g, 3.96 mmol) , 2-(2-chloroethyl)-1H-1,3-benzodiazole hydrochloride (1.12 g, 5.15 mmol) and DIPEA (10.6 ml, 59.45 mmol) were added to a solution in DMF (60 ml). .. The reaction mixture was allowed to stir at 30° C. for 6 days (reaction monitored by LCMS). The mixture was concentrated in vacuo and the residue was neutralized with saturated NaHCO ₃ (aq). The aqueous layer was extracted with 4:1 CHCl ₃ /IPA (4×100 ml), the combined organic layers were dried (MgSO ₄ ), filtered and evaporated in vacuo. The crude residue was flash column chromatographed (kp-NH, elution with a gradient of 60-100% EtOAc/heptane followed by 0-20% MeOH/EtOAc) followed by neutral reverse phase column chromatography (gradient elution 0-60. Purification by %MeCN/water) gave the title compound (0.173 g, 10%) as a yellow oil.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.31 (d, J=4.6Hz, 1H), 8.02(s, 1H), 7.57(t, J=9. 1 Hz, 1H), 7.45-7.40 (m, 2H), 7.36 (dd, J=8.6, 4.3 Hz, 1H), 7.17 (dd, J=6.0, 3) .2 Hz, 2 H), 4.68 (s, 2 H), 3.26 (d, J=6.8 Hz, 2 H), 3.15-3.07 (m, 6 H)
HPLCMS (Method D): [m/z]: 425.1 [M+H] ^+.
2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3 -Thiazole-4-carboxamide trihydrochloride (Example compound No. 94-HCl salt)

4M HCl in 1,4-dioxane (2.38 ml, 9.82 mmol) was added to 2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-. Add N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide (Example Compound #94) (1.30 g, 2.98 mmol) to a solution in MeOH (15 ml). And the reaction mixture was stirred at room temperature for 2 hours. The mixture was evaporated in vacuo to give the title compound (1.16g, 70%) as an off-white solid.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.48 (s, 1H), 8.25 (s, 1H), 8.07 (s, 1H), 7.79 (dt, J. =6.9, 3.4 Hz, 2H), 7.73 (s, 1H), 7.61 (dd, J=6.2, 3.1 Hz, 2H), 4.91 (s, 2H), 3 0.82 (s, 4H), 3.75 (t, J=6.4Hz, 2H), 3.61 (t, J=6.4Hz, 2H)
HPLCMS (Method D): [m/z]: 425.1 [M+H] ^+.
tert-Butyl 2-[({2-[4-(benzylcarbamoyl)-1,3-thiazol-2-yl]ethyl}amino)methyl]-5-methyl-1H-1,3-benzodiazol-1 -Carboxylate (116)

To a solution of 2-(2-aminoethyl)-N-benzyl-1,3-thiazole-4-carboxamide (104) (186 mg, 0.71 mmol) in DMF (5 ml) was added DIPEA (0.138 ml, 1 mmol), Subsequently tert-butyl 2-(chloromethyl)-5-methyl-1H-1,3-benzodiazol-1-carboxylate (F) (200 mg, 0.71 mmol) was added and the reaction was stirred at 90°C. Heated. After completion (LCMS), the mixture was concentrated in vacuo. The residue was purified by flash column chromatography (DCM/MeOH, eluting with 95:5) as a yellow oil (85 mg, 24%).

_{1H-NMR (CDCl 3, 400MHz} ): d [ppm] = 7.95 (s, 1H), 7.61 (s, 1H), 7.31 (dd, J = 24.4,4.2Hz, 6H ), 7.07 (d, J=8.2 Hz, 1H), 4.61 (d, J=6.1 Hz, 2H), 4.58 (s, 2H), 3.74 (t, J=6). .6 Hz, 2H), 3.20 (t, J=6.6 Hz, 2H), 2.46 (s, 3H), 1.36 (s, 9H),
HPLC MS (Method I): [m/z]: 506.6 [M+H] ^+.
tert-Butyl 2-[({2-[4-(benzylcarbamoyl)-1,3-thiazol-2-yl]ethyl}amino)methyl]-5-methoxy-1H-1,3-benzodiazol-1 -Carboxylate (117) and N-benzyl-2-(2-{[(5-methoxy-1H-1,3-benzodiazol-2-yl)methyl]amino}ethyl)-1,3-thiazole- 4-carboxamide (118)

In a similar manner to general procedure 7 under argon at 90° C. for 18 hours in MeCN (30 ml) 2-(2-aminoethyl)-N-benzyl-1,3-thiazole-4-carboxamide (104) ( 0.4 g, 2 mmol), tert-butyl 2-(chloromethyl)-5-methoxy-1H-1,3-benzodiazole-1-carboxylate (F) (0.45 g, 2 mmol), DIPEA (0. 4 g, 3 mmol) and NaI (0.23 g, 2 mmol) after purification by flash column chromatography (eluting with gradient DCM/MeOH 5-7%), with a red solid, (boc deprotected product, 350 mg, 27%). A mixture of expected products (133 mg, 21%) as a white solid was obtained.

HPLC MS (Method I): [m/z]: 522.6 [M+H] ⁺ and 422.6 [M+H] ^+.
2-{2-[(1,3-benzoxazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide (implemented Example compound #115)

2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide in a similar manner to general procedure 7 at 30° C. for 24 hours. Dihydrochloride (103) (300 mg, 0.735 mmol), 2-(chloromethyl)-1,3-benzoxazole (160 mg, 0.956 mmol), DIPEA (1.922 ml, 11.03 mmol) and DMF (15 ml). After purification by basic preparative HPLC, the title compound (102 mg, 34%) was obtained as a yellow oil.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.30 (d, J=4.7Hz, 1H), 8.08(s, 1H), 7.66-7.62(m, 1H), 7.60-7.54(m, 2H), 7.39-7.32(m, 3H), 4.77(d, J=1.6Hz, 2H), 4.14(s, 2H), 3.27 (d, J=6.3 Hz, 2H), 3.18 (t, J=6.6 Hz, 2H)
HPLCMS (Method D): [m/z]: 412.1 [M+H] ^+.
2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-(pyridin-2-ylmethyl)-1,3-thiazole-4-carboxamide (Example compound No. 58)

In a similar manner to General Procedure 7, 2-(2-aminoethyl)-N-(pyridin-2-ylmethyl)-1,3-thiazole-4-carboxamide dihydrochloride (105) (10) in DMF (10 ml). 240 mg, 0.72 mmol), 2-(2-chloroethyl)-1H-1,3-benzodiazole (259 mg, 1.43 mmol) and DIPEA (2.17 ml, 12.53 mmol) for basic preparative HPLC, The title compound (64 mg, 22%) was obtained as a brown solid after subsequent purification by flash column chromatography (eluting with 0-10% MeOH/DCM followed by a gradient of 0.8 M ammonia in MeOH/DCM).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.87 (t, J=6.0 Hz, 1H), 8.50 (d, J=4.6 Hz, 1H), 8.10( s, 1H), 7.74 (td, J=7.7, 1.7Hz, 1H), 7.44 (s, 2H), 7.33-7.21 (m, 2H), 7.10( dd, J=5.9, 3.2 Hz, 2H), 4.55 (d, J=6.0 Hz, 2H), 3.15 (t, J=6.7 Hz, 2H), 3.02(t , J=6.7 Hz, 2H), 2.90-2.96 (m, 4H)
HPLC MS (Method G): [m/z]: 407.2 [M+H] ^+.
2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl](methyl)amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]- 1,3-thiazole-4-carboxamide trihydrochloride (Example compound No. 112)

2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3 - thiazole-4-carboxamide trihydrochloride (example compound 94 _No.) (114mg, _0.205mmol), was Et 3 N (0.143ml, 1.025mmol) and DMF (1 ml) was stirred at room temperature for 1 hour. MeI (0.059 ml, 0.949 mmol) was added and stirred at room temperature for 140 hours. Water (10 ml) was added and the solvent removed in vacuo. The crude product was purified by basic preparative HPLC to give the free base (18 mg). MeOH (2 ml) and 4M HCl in dioxane (0.05 ml, 0.205 mmol) were added and stirred at room temperature for 2 hours. The reaction was concentrated in vacuo to give the title compound (24 mg, 21%) as a yellow solid.

1H-NMR (methanol-d4, 500 MHz): d[ppm]=8.48 to 8.39 (br m, 1H), 8.26 (s, 1H), 8.02 to 7.84 (br m, 1H), 7.82~7.76 (m, 2H ), 7.67~7.54 (m, 3H), 4.84 (s, 2H, obscured by _{H 2} O peak), 3.99～ 3.84 (m, 6H), 3.71 (t, J=6.8Hz, 2H), 3.16 (s, 3H)
HPLCMS (Method D): [m/z]: 439.1 [M+H] ^+.
2-{2-[2-(1H-1,3-benzodiazol-2-yl)acetamido]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole- 4-carboxamide dihydrochloride (Example compound No. 113)

2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole in THF (20 ml) for 2 hours at room temperature in a manner similar to general procedure 6. -4-Carboxamide dihydrochloride (103) (150 mg, 0.368 mmol), 2-(1H-1,3-benzodiazol-2-yl)acetic acid (114 mg, 0.552 mmol), DIPEA (0.384 ml, The free base compound (73 mg) was obtained after purification by basic preparative HPLC with 2.206 mmol) and HATU (210 mg, 0.52 mmol). The free base and 12M HCl (2 ml) in MeOH (6 ml) were stirred at room temperature for 2 hours. The reaction was concentrated in vacuo to give the title compound (97mg, 51%) as a brown solid.

¹ H NMR (Methanol-d4,500 MHz): d[ppm]=8.60 (dd, J=5.5, 1.2 Hz, 1 H), 8.32 (td, J=8.9, 1.1 Hz). , 1H), 8.15 (s, 1H), 7.96-7.90 (m, 1H), 7.81-7.75 (m, 2H), 7.63-7.58 (m, 2H). ), 4.93 (d, J=1.1 Hz, 2H), 4.27 (s, 2H), 3.76 (t, J=6.7 Hz, 2H), 3.32 (t, J=6). 0.6Hz, 2H)
HPLCMS (Method D): [m/z]: 439.1 [M+H] ^+.
2-{2-[(Cyclopropylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide (119)

2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole in MeOH (7 ml) for 16 hours at room temperature in a manner similar to general procedure 3. -4-Carboxamide dihydrochloride (103) (56% purity, 500 mg, 0.793 mmol), cyclopropanecarbaldehyde (67 mg, 0.951 mmol) and DIPEA (0.552 ml, 3.17 mmol) followed by NaBH ₄ ( 45 mg, 1.19 mmol) was added to give the title compound (149 mg, 51%) as a colorless oil after purification by flash column chromatography (kp-NH, eluting with a gradient of 0-10% MeOH/DCM). Was given.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.65 (t, J=5.7 Hz, 1H), 8.39 (dt, J=4.5, 1.3 Hz, 1H), 8.12 (s, 1H), 7.71 (ddd, J = 10.0, 8.3, 1.3Hz, 1H), 7.41 (dt, J = 8.6, 4.5Hz, 1H) , 4.66 (dd, J=5.7, 1.4 Hz, 2H), 3.13 (t, J=6.7 Hz, 2H), 2.92 (t, J=6.7 Hz, 2H), 2.43 (d, J=6.6 Hz, 2H), 1.92 (s, 1H), 0.93-0.81 (m, 1H), 0.43-0.35 (m, 2H), 0.13-0.06 (m, 2H)
HPLC MS (Method F): [m/z]: 335.8 [M+H] ^+.
2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl](cyclopropylmethyl)amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl ]-1,3-thiazole-4-carboxamide (Example compound No. 148)

In a similar manner to General Procedure 7, 2-{2-[(cyclopropylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1, for 32 hours at 30°C. 3-Thiazole-4-carboxamide (119) (149 mg, 0.45 mmol), 2-(2-chloroethyl)-1H-1,3-benzodiazole hydrochloride (116 mg, 0.53 mmol) and DIPEA (0.4 ml). , 2.23 mmol) after purification by basic preparative HPLC followed by flash column chromatography (eluting with a gradient of 0-10% MeOH in DCM then 0-10% 7M ammonia in MeOH/DCM). (5 mg, 2%) was obtained as a yellow oil.

1H-NMR (acetone-d6, 500 MHz): d[ppm]=8.48 (s, 1H), 8.39 (d, J=4.7 Hz, 1H), 7.98 (s, 1H), 7 .66 to 7.54 (m, 1H), 7.49 to 7.33 (m, 3H), 7.10 (dd, J=6.0, 3.2 Hz, 2H), 4.75 (dd, J=5.3, 1.5 Hz, 2H), 3.33 (t, J=6.7 Hz, 2H), 3.30 to 3.11 (m, 6H), 2.67 (d, J=6). 0.7 Hz, 2H), 1.10 to 0.94 (m, 1H), 0.60 to 0.43 (m, 2H), 0.26 to 0.22 (m, 2H)
HPLC MS (Method B): [m/z]: 479.2 [M+H] ^+.
2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-(pyridazin-3-ylmethyl)-1,3-thiazole-4-carboxamide Trihydrochloride (Example compound No. 122)

2-(2-Aminoethyl)-N-(pyridazin-3-ylmethyl)-1,3-thiazole-4-carboxamide in DMF (5 ml) in a similar manner using general procedure 7 for 5 days at room temperature. Dihydrochloride (106) (409 mg, 1.22 mmol), 2-(2-chloroethyl)-1H-1,3-benzodiazole hydrochloride (316.9 mg, 1.46 mmol) and DIPEA (3.18 ml, 0). .02 mol) gave the free base product after purification by flash column chromatography with gradient elution from 0-20% MeOH/DCM, followed by further purification by basic preparative HPLC.

The free base product was redissolved in MeOH (5 ml) and treated with 12M HCl (1 ml) for 1 hour to give the title compound (132 mg, 21%) as a pale yellow solid.

1H-NMR (Methanol-d4,500MHz): d[ppm]=9.52 (dd, J=5.2, 1.2Hz, 1H), 8.59 (dd, J=8.7, 1.2Hz). , 1H), 8.46 (dd, J=8.7, 5.2 Hz, 1H), 8.28 (s, 1H), 7.83 (dd, J=6.2, 3.1 Hz, 2H) , 7.65 (td, J=6.2, 5.5, 2.2 Hz, 2H), 5.04 (s, 2H), 3.90-3.82 (m, J=4.2 Hz, 4H). ), 3.79 (t, J=6.4 Hz, 2H), 3.64 (t, J=6.4 Hz, 2H)
HPLC MS (method C): [m/z]: 408.2 [M+H] ^+.
2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-(pyrimidin-2-ylmethyl)-1,3-thiazole-4-carboxamide Trihydrochloride (Example compound No. 129)

In a similar manner to General Procedure 7 for 9 days at room temperature 2-(2-aminoethyl)-N-(pyrimidin-2-ylmethyl)-1,3-thiazole-4-carboxamide diamine in DMF (10 ml). Hydrochloride (108) (300 mg, 0.89 mmol), 2-(2-chloroethyl)-1H-1,3-benzodiazole hydrochloride (193.7 mg, 0.89 mmol) and DIPEA (3.11 ml, 17. 8 mmol) gave the free base product after purification by flash column chromatography (eluting with a gradient of 0-40% MeOH/DCM) followed by further purification by basic preparative HPLC.

The free base product was redissolved in MeOH (5 ml) and treated with 12M HCl for 30 minutes to give the title compound (26 mg, 6%) as a pale yellow solid.

1H-NMR (D ₂ O, 500 MHz): d[ppm]=8.66 (d, J=5.1 Hz, 2H), 8.15 (s, 1H), 7.67 (dt, J=6. 7,3.4 Hz, 2H), 7.53 (td, J=6.2, 5.5, 2.1 Hz, 2H), 7.40 (t, J=5.1 Hz, 1H), 4.60 (S, 2H), 3.76-3.65 (m, 6H), 3.54 (t, J=6.4Hz, 2H)
HPLC MS (Method E): [m/z]: 408.1 [M+H] ^+.
General Procedure 8: 2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(5-methylpyrimidin-2-yl)methyl ]-1,3-thiazole-4-carboxamide (Example compound No. 155)

DBU (15.37 μl, 0.1 mmol) was added to 2-(2-aminoethyl)-N-[(5-methylpyrimidin-2-yl)methyl]-1,3-thiazole-4-carboxamide dihydrochloride ( 109) (36 mg, 0.1 mmol) was added to a suspension in MeCN (3 ml). N-(2-Nitrophenyl)prop-2-enamide (D) (19 mg, 0.1 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction was diluted with EtOAc (5 ml), washed with 10% NaHCO ₃ (5 ml), water (5 ml), brine (5 ml), dried (MgSO 4 ), filtered and evaporated to give the crude intermediate. Obtained and this was further reacted with iron powder (3 mg, 0.05 mmol) in AcOH (3 ml) at 80° C. for 3 hours. The reaction mixture was diluted with water (5 ml) then made basic by the slow addition of 10M NaOH (aq). The mixture was then further diluted with water (10 ml) and extracted with 4:1 chloroform/IPA (4 x 30 ml). The combined organic layer was separated, dried (MgSO _4), and evaporated in vacuo. The crude material was purified by basic preparative HPLC to give the title compound (8 mg, 67%) as a colorless film.

1H-NMR (Acetone-d6, 500 MHz): d[ppm]=8.58 (s, 2H), 8.44 (s, 1H), 8.03 (s, 1H), 7.45 (s, 2H). ), 7.14-7.05 (m, 2H), 4.72 (d, J=4.3 Hz, 2H), 3.24 (t, J=6.5 Hz, 2H), 3.13 (m). , 4H), 3.07 (t, J=6.2 Hz, 2H), 2.29 (s, 3H).
HPLCMS (Method C): [m/z]: 422.0 [M+H] ^+.
N-{5H,6H,7H-Cyclopenta[b]pyridin-7-yl}-2-[2-({2-[(2-nitrophenyl)carbamoyl]ethyl}amino)ethyl]-1,3-thiazole -4-carboxamide (Example compound 158)

In a manner similar to general procedure 8, 2-(2-aminoethyl)-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl}-1,3-thiazole-in MeCN (8 ml). 4-Carboxamide dihydrochloride (110) (660 mg, 1.83 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (344 mg, 1.79 mmol) and DBU (0.8 ml, 5.37 mmol). ) Afforded a crude intermediate which was further reacted with iron powder (180 mg, 3.22 mmol) in AcOH (10 ml) with flash column chromatography (5/10% gradient of 3M ammonia in MeOH/DCM). After elution) and subsequent purification by basic preparative HPLC, the title compound (176 mg, 25%) was obtained as a pale yellow foam.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.27 (d, J=4.7 Hz, 1H), 8.17 (s, 1H), 8.07 (br s, 1H), 7 .43 (br s, 2H), 7.37-7.32 (m, 1H), 7.19 (dt, J=8.5, 4.4Hz, 1H), 7.15-7.11 (m , 2H), 4.73 (dd, J=5.0, 1.3 Hz, 2H), 3.18 (t, J=6.2 Hz, 2H), 3.17-3.08 (m, 4H). , 3.04 (t, J=6.2Hz, 2H)
HPLC MS (Method C): [m/z]: 433.2 [M+H] ^+.
2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(6-methylpyridazin-3-yl)methyl]-1,3 -Thiazole-4-carboxamide (Example compound 174)

2-(2-Aminoethyl)-N-[(6-methylpyridazin-3-yl)methyl]-1,3-thiazole in MeCN (15 ml) for 2 hours at room temperature in a manner similar to general procedure 8. -4-carboxamide dihydrochloride (107) (382 mg, 0.932 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (161 mg, 0.839 mmol) and DBU (0.300 ml, 2. 01 mmol) by flash column chromatography (0-3% MeOH/DCM), followed by a second purification using an isolute silica column with a gradient of 0-2% 7M NH ₃ /MeOH in DCM. The Michael intermediate (163 mg, 31%) was obtained as a yellow oil.

The Michael intermediate (163 mg, 0.288 mmol) was reacted with iron powder (32 mg) in AcOH (3 ml) at 80° C. for 1 hour after purification by basic preparative HPLC followed by kp-NH silica column chromatography. The title compound (15 mg, 12%) was obtained as a beige solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=9.00 (t, J=6.0 Hz, 1H), 8.10 (s, 1H), 7.52-7.42 (m, 4H), 7.13-7.09 (m, 2H), 4.70 (d, J=6.1Hz, 2H), 3.15 (t, J=6.7Hz, 2H), 3.04-. 3.00 (m, 2H), 3.00-2.94 (m, 4H), 2.59 (s, 3H)
HPLCMS (Method B): [m/z]: 422.2 [M+H] ^+.
2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-methyl -1,3-thiazole-4-carboxamide (Example compound No. 165)

In a similar manner to general procedure 8 at room temperature for 16 hours 2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-methyl-1 in MeCN (20 ml). , 3-thiazole-4-carboxamide dihydrochloride (113) (528 mg, 1.44 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (276 mg, 1.44 mmol) and DBU (0. 64 ml, 0 mol) afforded the crude Michael intermediate (50%, 697 mg, 0.72 mmol), which was then reacted with iron powder (40 mg) in AcOH (4 ml) at 80° C. for 1.5 h. After flash column chromatography eluting with 2-40% MeOH in DCM, followed by purification by preparative HPLC, the title compound (99 mg, 32%) was obtained as a pale yellow solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.57 (t, J=5.6 Hz, 1H), 8.38 (dt, J=4.3, 1.3 Hz, 1H), 7.73-7.66 (m, 1H), 7.45 (dd, J=5.7, 3.2Hz, 2H), 7.40 (dt, J=8.6, 4.4Hz, 1H) , 7.13-7.08 (m, 2H), 4.61 (d, J=5.5 Hz, 2H), 3.06 (q, J=6.3 Hz, 4H), 2.97 (q, J=6.7 Hz, 4H), 2.60 (s, 3H)
HPLCMS (Method C): [m/z]: 439.2 [M+H] ^+.
2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-5-methyl-N-(pyrimidin-2-ylmethyl)-1,3-thiazole -4-carboxamide (Example compound 188)

In a similar manner to general procedure 8, 2-(2-aminoethyl)-5-methyl-N-(pyrimidin-2-ylmethyl)-1,3-thiazole-4 in MeCN (12 ml) at room temperature for 3 hours. -Carboxamide dihydrochloride (114) (315 mg, 0.594 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (114 mg, 0.594 mmol) and DBU (0.266 ml, 1.781 mmol). Gave the required Michael intermediate (142 mg, 42%) as a yellow oil after purification using an isolute silica column eluting with a gradient of 0-6% MeOH in DCM.

Reaction of Michael intermediate (142 mg, 0.248 mmol) with iron powder (42 mg) in AcOH (3 ml) at 80° C. for 1.5 h, basic preparative HPLC followed by a gradient of 0-8% MeOH in DCM. After purification by isolute silica column chromatography eluting with, the title compound (7 mg, 7%) was obtained as a brown solid.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.72 (d, J=4.9Hz, 2H), 7.43 (dt, J=6.6, 3.3Hz, 2H), 7.35(t, J=4.9Hz, 1H), 7.19(dt, J=6.0, 3.4Hz, 2H), 4.65(s, 2H), 3.24(t, J =6.8 Hz, 2H), 3.22-3.17 (m, 4H), 3.15 (t, J=6.6Hz, 2H), 2.68 (s, 3H).
HPLCMS (Method D): [m/z]: 422.2 [M+H] ^+.
Benzyl N-(3-{[2-(1H-1,3-benzodiazol-2-yl)ethyl][2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}- 1,3-thiazol-2-yl)ethyl]amino}propyl)carbamate (Example compound 179)

In a similar manner to General Procedure 3, 2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl) in MeOH (1 ml) at room temperature for 1 hour. -N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide (Example compound 94-free base) (166 mg, 0.391 mmol), benzyl (3-oxopropyl) ) Carbamate (97 mg, 0.469 mmol) and DIPEA (0.12 ml, 0.587 mmol) followed by NaBH ₄ (22 mg, 0.587 mmol) were added to flash chromatography (0-5% MeOH/DCM gradient). After purification by elution), the title compound (94 mg, 39%) was obtained as a pale yellow oil.

HPLC MS (Method F): [m/z]: 616.2 [M+H] ^+.
2-{2-[(3-aminopropyl)[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino]ethyl}-N-[(3-fluoropyridin-2-yl) Methyl]-1,3-thiazole-4-carboxamide (Example compound No. 163)

Benzyl N-(3-{[2-(1H-1,3-benzodiazol-2-yl)ethyl][2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}- 1,3-Thiazol-2-yl)ethyl]amino}propyl)carbamate (Example compound 179) (45 mg, 0.073 mmol) in AcOH/HBr (1:1, 1 ml) at 50° C. for 2 hours. It was stirred. The reaction mixture was evaporated in vacuum. Purification by basic preparative HPLC gave the title compound (16 mg, 45%) as a colorless oil.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.32(d, J=4.7Hz, 1H), 7.90(s, 1H), 7.63-7.52(m, 1H), 7.44 (dt, J=6.6, 3.3 Hz, 2H), 7.35 (dt, J=8.6, 4.4 Hz, 1H), 7.17 (dt, J=6) 0.0, 3.3 Hz, 2H), 4.75 (d, J=1.5 Hz, 2H), 3.20 (t, J=6.6 Hz, 2H), 3.04 (s, 4H), 2 .98 (t, J=6.6 Hz, 2H), 2.65 (m, 4H), 1.67 (m, 2H)
HPLC MS (Method D): [m/z]: 482.2 [M+H] ^+.
2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl](butyl)amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]- 1,3-thiazole-4-carboxamide (Example compound 157)

In a similar manner to General Procedure 3, 2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl) in MeOH (1 ml) at room temperature for 1 hour. -N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide (Example compound No. 94-free base) (60 mg, 0.141 mmol), butanal (12 mg, 0. 174 mmol) and DIPEA (98 μl, 0.56 mmol) followed by NaBH ₄ (8 mg, 0.21 mmol) gave the title compound (50 mg, 73%) as a yellow oil after purification by basic preparative HPLC. It was

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.13 (s, 1H), 8.66 (t, J=5.6 Hz, 1H), 8.37 (d, J=4. 7Hz, 1H), 8.06 (s, 1H), 7.69 (ddd, J=9.9, 8.4, 1.2Hz, 1H), 7.57-7.32 (m, 3H), 7.17-7.01 (m, 2H), 4.65 (d, J = 4.6Hz, 2H), 3.17 (t, J = 6.7Hz, 2H), 2.96 (m, 4H) ), 2.88 (t, J=6.7 Hz, 2H), 2.58-2.51 (m, 2H), 1.40 (m, 2H), 1.23 (m, 2H), 0. 83 (t, J=7.4Hz, 3H)
HPLCMS (Method D): [m/z]: 481.3 [M+H] ^+.
2-(2-{bis[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1, 3-thiazole-4-carboxamide (Example compound No. 152)

In a similar manner to General Procedure 7, 2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl in DMF (5 ml) for 3 days at 30°C. ) -N-[(3-Fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide (Example compound No. 94-free base) (400 mg, 1.13 mmol), 2-(2- Chloroethyl)-1H-1,3-benzodiazole hydrochloride (492 mg, 2.27 mmol) and DIPEA (3.03 ml, 17 mol) by basic preparative HPLC followed by flash column chromatography (0-10% MeOH). /DCM followed by a gradient of 0-10% 7N ammonia in MeOH/DCM) and a second purification by basic preparative HPLC afforded the title compound (10 mg, 1.5%) as an off-white solid. ..

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.28 (s, 1H), 8.66 (t, J=5.7 Hz, 1H), 8.37 (dt, J=4. 6,1.4 Hz, 1 H), 8.06 (s, 1 H), 7.69 (ddd, J=10.0, 8.3, 1.3 Hz, 1 H), 7.61-7.46 (m , 3H), 7.39 (dq, J=8.6, 4.2 Hz, 2H), 7.23-7.04 (m, 4H), 4.77-4.52 (m, 4H), 3 .27 (t, J=7.2 Hz, 2H), 3.15-3.04 (m, 2H), 3.02-2.90 (m, 4H), 2.87 (t, J=6. 7Hz, 2H)
HPLCMS (Method B): [m/z]: 569.3 [M+H] ^+.
2-{2-[bis(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4 -Carboxamide (Example compound No. 166)

In a similar manner to General Procedure 7, 2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino in DMF (1 ml) at 45° C. for 3 hours, then 55° C. for 1 hour. ] Ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide (Example Compound No. 40) (110 mg, 0.268 mmol), 2-(chloromethyl) -1H-1,3-benzodiazole (45 mg, 0.268 mmol), DIPEA (0.467 ml, 2.68 mmol) by basic preparative HPLC followed by flash column chromatography (0-10% MeOH/DCM). After purification by elution with a gradient of 0-10% 7N ammonia in MeOH/DCM), the title compound (10 mg, 7%) was obtained as a white solid.

1H-NMR (Acetone-d6,500MHz): d[ppm]=11.99(s,1H),8.43(s,1H),8.33(d,J=4.7Hz,1H),8 .02 (s, 1H), 7.71-7.55 (m, 3H), 7.51 (s, 2H), 7.37 (dt, J=8.5, 4.4Hz, 1H), 7 .17 (d, J=5.7 Hz, 4H), 4.80-4.70 (m, 2H), 4.17 (s, 4H), 3.37 (t, J=6.9 Hz, 2H) , 3.20 (t, J=6.9 Hz, 2H)
HPLCMS (Method B): [m/z]: 541.3 [M+H] ^+.
2-(2-{[2-(4-Fluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl] -1,3-thiazole-4-carboxamide (Example compound No. 243)

In a manner similar to general procedure 8, 2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazol-4-carboxamidediamine in MeCN (10 ml). By the hydrochloride salt (103) (662 mg, 1.87 mmol), N-(3-fluoro-2-nitrophenyl)prop-2-enamide (G) (394 mg, 1.87 mmol) and DBU (924 μl, 6.18 mmol). The crude intermediate was obtained, which was further reacted with iron powder (286 mg, 5.12 mmol) in AcOH (15 ml) for basic preparative HPLC followed by flash column chromatography (0-20% MeOH/DCM). After purification by gradient elution), the title compound (203 mg, 34%) was obtained as a white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.66 (t, J=5.6 Hz, 1H), 8.39 (dt, J=4.7, 1.3 Hz, 1H), 8.08 (s, 1H), 7.70 (ddd, J=10.0, 8.4, 1.1 Hz, 1H), 7.40 (dt, J=8.7, 4.4 Hz, 1H) , 7.27 (d, J=8.0 Hz, 1H), 7.10 (td, J=8.0, 4.9 Hz, 1H), 6.92 (dd, J=11.1, 8.0 Hz) , 1H), 4.68-4.62 (m, 2H), 3.16 (t, J=6.7Hz, 2H), 3.05 (t, J=6.7Hz, 2H), 2.99. (T, J=6.6Hz, 4H)
HPLCMS (Method B): [m/z]: 443.2 [M+H] ^+.
2-(2-{[(4-fluoro-1H-1,3-benzodiazol-2-yl)methyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1 , 3-oxazole-4-carboxamide (Example compound No. 253)

In a manner similar to general procedure 7, 2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4- in DMF (2.5 ml). Carboxamide dihydrochloride (235) (100 mg, 0.3 mmol), 2-(chloromethyl)-7-fluoro-1H-1,3-benzodiazole hydrochloride (66 mg, 0.3 mmol) and DIPEA (258 μl, 1 When .48Mmol) is stirred 73 hours at 40 ° C., reverse phase Biotage (a = water _{/0.1%NH 3; B = MeCN / 0.1} % NH 3; 10% a / B is 2 column volumes, 10 After purification by elution with a gradient of 4 column volumes for 30% A/B, 10 column volumes for 30-60% A/B, and 5 column volumes for 60-100%, the title compound (23 mg, 18%) was brown glass. Obtained as a solid.

1H-NMR (DMSO-d6,500MHz): d[ppm]=12.49 (brs, 1H), 8.54-8.47 (m, 2H), 8.39-8.34 (m, 1H). ), 7.73-7.65 (m, 1H), 7.42-7.37 (m, 1H), 7.34-7.24 (m, 1H), 7.15-7.06 (m. , 1H), 6.92 (t, 1H), 4.63-4.57 (m, 2H), 3.99-3.91 (m, 2H), 3.02-2.94 (m, 4H). ), 2.63 (br s, 1H)
HPLC MS (Method D): [m/z]: 413.2 [M+H] ^+.
2-(2-{[(4-fluoro-1H-1,3-benzodiazol-2-yl)methyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1 , 3-thiazole-4-carboxamide (Example compound 274)

In a similar manner to General Procedure 7, 2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazol-4- in DMF (5.5 ml). Carboxamide dihydrochloride (103) (200 mg, 0.57 mmol), 2-(chloromethyl)-7-fluoro-1H-1,3-benzodiazole hydrochloride (125 mg, 0.57 mmol) and DIPEA (493 μl, 2 .83 mmol) was heated at 40° C. for 18 hours, stirred at room temperature for 2 days, then heated at 40° C. for 4 hours and subjected to reverse phase chromatography [(10-100% (water+0.1% ammonia)/(MeCN+0). After elution with a gradient of 0.1% ammonia), the title compound (7 mg, 3%) was obtained as a glassy brown solid.

1H-NMR (DMSO-d6,500MHz): d[ppm]=12.50 (s, 1H), 8.70-8.61 (m, 1H), 8.39-8.32 (m, 1H). , 8.13 (s, 1H), 7.72-7.66 (m, 1H), 7.42-7.36 (m, 1H), 7.34-7.25 (m, 1H), 7 .15-7.08 (m, 1H), 6.93 (m, 1H), 4.68-4.62 (m, 2H), 4.00-3.94 (m, 2H), 3.22. -3.15 (m, 2H), 3.01-2.93 (m, 2H), 2.71 (s, 1H)
HPLCMS (Method D): [m/z]: 429.1 [M+H] ^+.
General Scheme 6 above:
General Procedure 9: 2-{2-[(1H-1,3-benzodiazol-2-yl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3 -Thiazole-4-carboxamide dihydrochloride (Example compound No. 121)

2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide dihydrochloride (103) (1.65 g, 2.62 mmol, purity) 56%), 2-chloro-1H-benzimidazole (0.1 g, 0.66 mmol) and DIPEA (0.571 ml, 3.277 mmol) in n-butanol (3 ml) and MeOH (0.1 ml), Heated at 150° C. for 2.5 hours under microwave irradiation. The reaction mixture was concentrated in vacuo. The residue was dissolved in saturated NaHCO ₃ solution, diluted with water (20 ml) and extracted with 4:1 chloroform/IPA (4×20 ml). Dry the organic extracts combined (MgSO _4), filtered and evaporated in vacuo. The residue was purified by flash column chromatography (kp-NH, eluting with a gradient of 0-10% MeOH/EtOAc) followed by basic preparative HPLC. The resulting residue was dissolved in MeOH (4 ml) and treated with 12M HCl (1 ml) for 2 hours. Evaporation in vacuo gave the title compound (0.131g, 43%) as a white solid.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.60 (d, J=5.5Hz, 1H), 8.31(t, J=8.3Hz, 1H), 8.19( s, 1H), 7.93 (br, J=3.8 Hz, 1H), 7.38 (dt, J=7.1, 3.5 Hz, 2H), 7.28 (dd, J=5.9). , 3.2Hz, 2H), 4.93(s, 2H), 3.99(t, J=6.4Hz, 2H), 3.49(t, J=6.4Hz, 2H).
HPLCMS (Method D): [m/z]: 397.1 [M+H] ^+.
2-{3-[(1H-1,3-benzodiazol-2-yl)amino]propyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazol-4- Carboxamide (Example compound No. 135)

In a similar manner to General Procedure 9, 2-(3-aminopropyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-in the microwave for 1 hour at 150°C. 4-carboxamide dihydrochloride (115) (173 mg, 0.472 mmol), 2-chloro-1H-benzimidazole (60 mg, 0.393 mmol), DIPEA (0.21 ml, 1.18 mmol), n-BuOH (2 ml). After purification by basic prep-HPLC with and DMF (0.5 ml), the title compound (26 mg, 16%) was obtained as an off-white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=10.74 (s, 1H), 8.68 (t, J=5.7 Hz, 1H), 8.37 (dt, J=4. 7, 1.4 Hz, 1 H), 8.15 (s, 1 H), 7.70 (ddd, J=10.0, 8.3, 1.3 Hz, 1 H), 7.40 (dt, J=8) .6, 4.4 Hz, 1H), 7.11 (dd, J=14.8, 7.6 Hz, 2H), 6.96-6.75 (m, 2H), 6.67 (t, J= 5.7 Hz, 1 H), 4.65 (dd, J=5.7, 1.4 Hz, 2 H), 3.39 (q, J=6.7 Hz, 2 H), 3.18-3.07 (m , 2H), 2.07 (m, 2H)
HPLCMS (Method D): [m/z]: 411.2 [M+H] ^+.
General Scheme 7 above:
Ethyl 2-({[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}methyl)-1,3-thiazol-4-carboxylate (120)

In a similar manner to General Procedure 3, 2-(1H-benzimidazol-2-yl)ethanamine dihydrochloride (379 mg, 1.62 mmol), ethyl 2-formyl-1 in DCM (10 ml) at room temperature for 24 hours. , 3-Thiazol-4-carboxylate (300 mg, 1.62 mmol), DIPEA (1.13 ml, 6.48 mmol) and MgSO ₄ (100 mg) followed by NaBH ₄ (92 mg, 2.43 mmol) were added to flash. After purification by column chromatography (kp-NH, eluting with a gradient of 0-15% MeOH/EtOAc) the title compound (201 mg, 35%) was obtained as a white solid.

1H-NMR (DMSO-d6,500MHz): d[ppm]=12.17(s, 1H), 8.40(s, 1H), 7.51(d, J=7.8Hz, 1H), 7 .40 (d, J=7.1 Hz, 1H), 7.16-7.07 (m, 2H), 4.28 (q, J=7.1 Hz, 2H), 4.05 (m, 2H). , 3.04 (m, 2H), 2.99 (t, J = 5.8Hz, 2H), 2.52 (s, 2H), 1.29 (t, J = 7.1Hz, 3H)
HPLCMS (Method A): [m/z]: 331.0 [M+H]+
Ethyl 2-({[3-(1H-1,3-benzodiazol-2-yl)propyl]amino}methyl)-1,3-thiazol-4-carboxylate (121)

In a similar manner to general procedure 3 at room temperature for 24 hours 3-(1H-benzimidazol-2-yl)propan-1-amine (568 mg, 3.24 mmol), ethyl 2-formyl- in DCM (20 ml). Addition of 1,3-thiazole-4-carboxylate (600 mg, 3.24 mmol), DIPEA (2.26 ml, 12.96 mmol) and MgSO ₄ (300 mg), followed by NaBH ₄ (184 mg, 4.86 mmol), After purification by flash column chromatography (kp-NH, eluting with a gradient of 0-10% MeOH/EtOAc), the title compound (570 mg, 31%, 62% purity) was obtained as a white solid.

1H-NMR (DMSO-d6, 500MHz): d[ppm]=12.14(s, 1H), 8.39(s, 1H), 7.50(d, J=6.9Hz, 1H), 7 .39 (d, J=7.0 Hz, 1H), 7.14-7.05 (m, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.99 (m, 2H). , 2.87 (t, J=7.6 Hz, 2H), 1.94 (q, J=7.3 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H)
HPLCMS (Method A): [m/z]: 345.00 [M+H] ^+.
tert-Butyl 2-(2-{[(tert-butoxy)carbonyl]({[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]methyl})amino}ethyl)-1H-1,3 -Benzodiazole-1-carboxylate (122)

In a manner similar to General Procedure 4, ethyl 2-({[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}methyl)- in THF (10 ml) at room temperature for 20 hours. Flash column chromatography (40) by 1,3-thiazole-4-carboxylate (120) (201 mg, 0.608 mmol), Boc ₂ O (146 mg, 0.669 mmol) and TEA (0.08 ml, 0.608 mmol). The title compound (345 mg, 94%) was obtained as a colorless oil after purification by elution with a gradient of -100% EtOAc/Heptane).

HPLCMS (Method A): [m/z]: 531.15 [M+H] ^+.
tert-Butyl 2-(3-{[(tert-butoxy)carbonyl]({[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]methyl})amino}propyl)-1H-1,3 -Benzodiazole-1-carboxylate (123)

In a manner similar to General Procedure 4, ethyl 2-({[3-(1H-1,3-benzodiazol-2-yl)propyl]amino}methyl)- in THF (40 ml) at room temperature for 72 hours. 1,3-thiazole-4-carboxylate (121) (0.570 g, 1.018 mmol, purity 62%), Boc ₂ O (1.56 g, 7.124 mmol) and TEA (0.671 ml, 5.089 mmol). , Followed by further addition of Boc ₂ O (0.444 g, 2.036 mmol) for 4 hours, and further addition of Boc ₂ O (0.444 g, 2.036 mmol) for another 16 hours by flash column chromatography (0. After purification by elution with a gradient of ~60% EtOAc/heptane), the title compound (1.162 g, 48% pure, quantitative) was obtained as a yellow oil.

HPLC MS (Method A): [m/z]: 545.15 [M+H] ^+.
2-({[2-(1H-1,3-benzodiazol-2-yl)ethyl][(tert-butoxy)carbonyl]amino}methyl)-1,3-thiazole-4-carboxylic acid (124)

In a manner similar to general procedure 5, tert-butyl 2-(2-{[(tert-butoxy)carbonyl]({[4-(ethoxycarbonyl)-1,3-) in THF/water (25 ml/5 ml). Thiazol-2-yl]methyl})amino}ethyl)-1H-1,3-benzodiazol-1-carboxylate (122) (385 mg, 0.73 mmol) and LiOH (87 mg, 3.63 mmol). The compound (350 mg, 99%, 83% purity) was obtained as a white solid.

HPLCMS (Method A): [m/z]: 403.00 [M+H] ^+.
2-({[3-(1H-1,3-benzodiazol-2-yl)propyl][(tert-butoxy)carbonyl]amino}methyl)-1,3-thiazole-4-carboxylic acid (125)

In a manner similar to General Procedure 5, tert-butyl 2-(3-{[(tert-butoxy)carbonyl]({[4-(ethoxycarbonyl)-1,3-) in THF/water (20 ml/5 ml). Thiazol-2-yl]methyl})amino}propyl)-1H-1,3-benzodiazol-1-carboxylate (123) (1.16 g, 1.02 mmol, purity 48%) and LiOH (122 mg, 5 0.09 mmol) afforded the crude title compound (811 mg, 52% purity) as an off-white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.39 (s, 1H), 7.65 (br s, 2H), 7.37 (br s, 2H), 4.68 (br). s, 2H), 3.38 (br s, 2H), 3.00 (br s, 2H), 2.08 (br s, 2H), 1.34 (s, 9H)
HPLC MS (Method A): [m/z]: 417.05 [M+H] ^+.
tert-Butyl N-[2-(1H-1,3-benzodiazol-2-yl)ethyl]-N-[(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1 ,3-Thiazol-2-yl)methyl]carbamate (126)

In a manner similar to general procedure 6, 2-({[2-(1H-1,3-benzodiazol-2-yl)ethyl][(tert-butoxy)carbonyl]amino}methyl in DMF (4 ml). )-1,3-Thiazol-4-carboxylic acid (124) (175 mg, 0.36 mmol, purity 83%), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (108 mg, 0.54 mmol) ), DIPEA (0.25 ml, 1.44 mmol) and HATU (206 mg, 0.54 mmol) after purification by basic preparative HPLC to give the title compound (81 mg, 44%) as a colorless solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.24 (s, 1H), 8.75 (s, 1H), 8.36 (s, 1H), 8.22 (s, 1H). ), 7.73-7.66 (m, 1H), 7.50 (s, 1H), 7.46-7.37 (m, 2H), 7.11 (s, 2H), 4.72 ( s, 2H), 4.66 (d, J=4.4Hz, 2H), 3.76 (m, 2H), 3.20-3.05 (m, 2H), 1.30 (s, 9H).
HPLCMS (Method A): [m/z]: 511.10 [M+H] ^+.
tert-Butyl N-[3-(1H-1,3-benzodiazol-2-yl)propyl]-N-[(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1 ,3-Thiazol-2-yl)methyl]carbamate (127)

In a manner similar to general procedure 6, 2-({[3-(1H-1,3-benzodiazol-2-yl)propyl][(tert-butoxy)carbonyl]amino}methyl in DMF (4 ml). )-1,3-Thiazol-4-carboxylic acid (125) (406 mg, 0.51 mmol, purity 52%), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (152 mg, 0.76 mmol) ), DIPEA (0.36 ml, 2.04 mmol) and HATU (291 mg, 0.76 mmol) after purification by flash column chromatography (kp-NH, eluting with a gradient of 70-100% EtOAc/heptane). (215 mg, 75%) was obtained as a white solid.

1H-NMR (DMSO-d6,500MHz): d[ppm]=12.15(s, 1H), 8.68(t, J=5.5Hz, 1H), 8.36(s, 1H), 8 .22 (s, 1H), 7.69 (t, J=9.3 Hz, 1H), 7.52-7.45 (m, 1H), 7.42-7.34 (m, 2H), 7 0.09 (s, 2H), 4.71 (s, 2H), 4.65 (d, J=5.5 Hz, 2H), 3.41 (s, 2H), 2.81 (t, J=7) .3 Hz, 2H), 2.04 (m, 2H), 1.34 (s, 9H)
HPLC MS (Method A): [m/z]: 525.15 [M+H] ^+.
tert-Butyl N-[3-(1H-1,3-benzodiazol-2-yl)propyl]-N-[(4-{[(3,5-difluoropyridin-2-yl)methyl]carbamoyl} -1,3-Thiazol-2-yl)methyl]carbamate (128)

In a similar manner to general procedure 6, 2-({[3-(1H-1,3-benzodiazol-2-yl)propyl][(tert-butoxy) in DMF (3 ml) for 2 hours at room temperature. Carbonyl]amino}methyl)-1,3-thiazole-4-carboxylic acid (125) (0.146 g, 0.351 mmol), (3,5-difluoropyridin-2-yl)methanamine dihydrochloride (0.114 g) , 0.526 mmol), DIPEA (0.305 ml, 1.753 mmol) and HATU (0.227 g, 0.526 mmol) after purification by basic preparative HPLC to give the title compound (0.071 g, 37%) as a glass. Obtained as a solid.

¹ H NMR (DMSO-d6, 500 MHz): d[ppm]=12.14 (s, 1H), 8.73-8.66 (m, 1H), 8.47-8.41 (m, 1H). , 8.24-8.18 (m, 1H), 7.95-7.87 (m, 1H), 7.52-7.45 (m, 1H), 7.41-7.35 (m, 1H), 7.15-7.05 (m, 2H), 4.70 (s, 2H), 4.61 (d, J=5.7Hz, 2H), 3.45-3.38 (m, 2H), 2.85-2.77 (m, 2H), 2.07-1.99 (m, 2H), 1.34 (s, 9H).
HPLC MS (Method A): [m/z]: 543.15 [M+H] ^+.
2-({[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}methyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole -4-Carboxamide trihydrochloride (Example compound No. 118)

In a manner similar to general procedure 2, rt-butyl N-[2-(1H-1,3-benzodiazol-2-yl) in MeOH (5 ml) for 4 days at room temperature, then 40° C. for 4 hours. Ethyl]-N-[(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)methyl]carbamate (126) (81 mg, 0.159 mmol) and 12M HCl (0.53 ml) gave the title compound (49 mg, 58%) as a white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.81 (s, 1H), 8.41 (s, 1H), 8.36 (dt, J=4.7, 1.4 Hz, 1H), 7.78 (dd, J=6.1, 3.1 Hz, 2H), 7.72 (ddd, J=10.0, 8.4, 1.2 Hz, 1H), 7.53 (dd , J=6.0, 3.1 Hz, 2H), 7.40 (dd, J=8.4, 4.3 Hz, 1H), 4.73 (s, 2H), 4.69 (d, J= 5.1 Hz, 2H), 3.79 (br s, 2H), 3.73 (br s, 2H)
HPLCMS (Method D): [m/z]: 411.1 [M+H] ^+.
2-({[3-(1H-1,3-benzodiazol-2-yl)propyl]amino}methyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole -4-Carboxamide trihydrochloride (Example compound 119)

In a similar manner to General Procedure 2, 12M HCl (0.635 ml) was added to tert-butyl N-[3-(1H-1,3-benzodiazol-2-yl)propyl]-N-[(4 -{[(3-Fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)methyl]carbamate (127) (215 mg, 0.381 mmol) added to a solution in MeOH (5 ml). The mixture was stirred for 16 hours. Further 12M HCl (0.635 ml, 7.623 mmol) was added and the mixture was stirred for a further 20 hours. The reaction mixture was evaporated in vacuo to give the title compound (139mg, 68%) as a white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=9.96 (br s, 1H), 8.78 (br s, 1H), 8.40 (s, 1H), 8.38 (d). , J=4.4 Hz, 1H), 7.80-7.76 (m, 2H), 7.73 (t, J=8.1 Hz, 1H), 7.55-7.51 (m, 2H). , 7.44-7.39 (m, 1H), 4.70 (d, J=4.6 Hz, 2H), 4.64 (s, 2H), 3.35 (t, J=7.2 Hz, 2H), 3.23 (t, J=7.4Hz, 2H), 2.39-2.33 (m, 2H)
HPLC MS (Method D): [m/z]: 425.2 [M+H] ^+.
2-({[3-(1H-1,3-benzodiazol-2-yl)propyl]amino}methyl)-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3 -Thiazole-4-carboxamide dihydrochloride (Example compound No. 124)

In a manner similar to general procedure 2, 12M HCl (0.524 ml, 6.28 mmol) was added to tert-butyl tert-butyl N-[3-(1H-1,3-benzodiazol-2-yl)propyl. ]-N-[(4-{[(3,5-difluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)methyl]carbamate (128) (0.071 g, 0. Addition of 131 mmol) in MeOH (3 ml) at 45° C. for 4 h gave the title compound (0.036 g, 53%) as a white solid.

¹ H NMR (Methanol-d4,500 MHz): d[ppm]=8.37 (s, 1H), 8.35-8.30 (m, 1H), 7.81-7.76 (m, 2H). , 7.66-7.57 (m, 3H), 4.79 (s, 2H), 4.74 (s, 2H), 3.45-3.36 (m, 4H), 2.51-2. .41 (m, 2H)
HPLC MS (Method D): [m/z]: 443.2 [M+H] ^+.
General Scheme 8 above:
General Procedure 10: 3-Bromo-N-(2-nitrophenyl)propanamide (129).

3-Bromopropanoyl chloride (1.59 ml, 15.75 mmol) in ice-cooled solution of 2-nitroaniline (2.18 g, 15.75 mmol) and TEA (2.63 ml, 18.9 mmol) in toluene (50 ml). To the mixture and the mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo and the residue was triturated with water (10ml) to give a brown precipitate which was collected by filtration. Purification by flash column chromatography (eluting with a gradient of 0-10% EtOAc/heptane) gave the title compound (0.988 g, 23%) as a yellow crystalline solid.

_{1H-NMR (CDCl 3, 250MHz} ): d [ppm] = 10.45 (s, 1H), 8.81 (dd, J = 8.5,1.2Hz, 1H), 8.25 (dd, J =8.5, 1.6Hz, 1H), 7.78-7.61 (m, 1H), 7.24 (ddd, J = 8.5, 7.3, 1.3Hz, 1H), 3. 74 (t, J=6.5 Hz, 2H), 3.11 (t, J=6.5 Hz, 2H)
HPLC MS (Method A): [m/z]: 272.95/274.90 [M+H] ^+.
3-Bromo-N-(4-fluoro-2-nitrophenyl)propanamide (130)

In a manner similar to general procedure 10, 3-bromopropanoyl chloride (2.29 ml, 23.06 mmol), 4-fluoro-2-nitroaniline (3 g, 19.22 mmol) in toluene (35 ml) at room temperature for 40 hours. ) And TEA (3.124 ml, 23.06 mmol) after purification by flash column chromatography (eluting with a gradient of 0-40% EtOAc/heptane) to give the title compound (3.04 g, 42%) as a yellow solid. Was given.

1H-NMR (DMSO-d6,500MHz): d [ppm] = 10.38 (s, 1H), 7.91 (dd, J = 8.6, 2.5Hz, 1H), 7.65-7. 60 (m, 2H), 3.68 (t, J = 6.4Hz, 2H), 2.97 (t, J = 6.4Hz, 2H)
HPLC MS (Method A): [m/z]: 290.75/292.75 [M+H] ^+.
4-Bromo-N-(2-nitrophenyl)butanamide (131)

In a manner similar to General Procedure 10 4-bromobutanoyl chloride (1.56 ml, 13.48 mmol), 2-nitroaniline (1.55 g, 11.24 mmol) in toluene (25 ml) at room temperature for 16 hours. After purification by TEA (1.566 ml, 11.2 mmol) by flash column chromatography (eluting with a gradient of 0-40% EtOAc/heptane) the title compound (2.35 g, 41%) was obtained as a yellow oil. .

1H NMR (DMSO-d6, 500 MHz): d[ppm]=10.33 (s, 1H), 7.93 (dd, J=8.2, 1.4 Hz, 1H), 7.72 to 7.65. (M, 1H), 7.58 (dd, J=8.1, 1.2 Hz, 1H), 7.38 to 7.34 (m, 1H), 3.58 (t, J=6.6 Hz, 2H), 2.51 (t, J=6.6 Hz, 2H, unclear by DMSO), 2.13 to 2.06 (m, 2H).
HPLC MS (Method A): [m/z]: 288.75 [M+H] ^+.
General Procedure 11: Ethyl 2-[2-({2-[(2-nitrophenyl)carbamoyl]ethyl}amino)ethyl]-1,3-thiazole-4-carboxylate (132).

To a solution of 3-bromo-N-(2-nitrophenyl)propanamide (129) (1.04 g, 3.8 mmol) in DMF (10 ml) was added ethyl 2-(2-aminoethyl)-1,3-thiazole. 4-carboxylate hydrochloride was added dropwise over (1 g, 3.8 mmol, 90% purity) and _{Na 2 CO 3 (0.48g, 4.56mmol} ) and DMF (30 ml) in a mixture of 20 min. The reaction mixture was stirred at room temperature for 16 hours. Water (10 ml) was added and the mixture was extracted with EtOAc (3 x 20 ml). The combined organic extracts were washed with brine (10ml), dried (MgSO _4), filtered, and evaporated in vacuo to give the crude title compound (1.5g, 70%, 70% purity) was obtained , Which was used without purification.

HPLC MS (Method A): [m/z]: 393.1 [M+H] ^+.
Ethyl 2-[2-({2-[(4-fluoro-2-nitrophenyl)carbamoyl]ethyl}amino)ethyl]-1,3-thiazole-4-carboxylate (133)

In a similar manner to general procedure 11 at room temperature for 24 hours 3-bromo-N-(4-fluoro-2-nitrophenyl)propanamide (130) (1 g, 2.68 mmol), ethyl in DMF (10 ml). 2-(2-Aminoethyl)-1,3-thiazole-4-carboxylate hydrochloride (0.634 g, 2.68 mmol) and Na ₂ CO ₃ (0.426 g, 4.02 mmol) gave the crude title compound ( 2.26 g, 80%, purity 39%) was obtained, which was used without purification.

HPLCMS (Method A): [m/z]: 411 [M+H] ^+.
Ethyl 2-[2-({3-[(2-nitrophenyl)carbamoyl]propyl}amino)ethyl]-1,3-thiazole-4-carboxylate (134)

In a similar manner to general procedure 11 for 16 hours at room temperature 4-bromo-N-(2-nitrophenyl)butanamide (131) (2.35 g, 4.65 mmol) ethyl 2-(2-aminoethyl). 3-thiazol-4-carboxylic carboxylate hydrochloride _{(1.10g, 4.66mmol), Na 2} CO 3 (0.74g, 6.98mmol) and the DMF (25 ml), the crude title compound (3. 0 g, quantitative) was obtained as a yellow oil which was used in the next step without further purification.

HPLCMS (Method A): [m/z]: 407 [M+H] ^+.
Ethyl 2-(2-{[(tert-butoxy)carbonyl]({2-[(2-nitrophenyl)carbamoyl]ethyl})amino}ethyl)-1,3-thiazole-4-carboxylate (135)

In a manner similar to general procedure 4, ethyl 2-[2-({2-[(2-nitrophenyl)carbamoyl]ethyl}amino)ethyl]-1,3-thiazole-4-carboxy in THF (50 ml). Rate (132) (1.3 g, 1.99 mmol, purity 60%), Boc ₂ O (477 mg, 2.19 mmol) and TEA (413 μl, 2.9 mmol) were stirred at room temperature for 16 hours. Further Boc ₂ O (477 mg, 2.19 mmol) and TEA (413 μl, 2.98 mmol) were added and the mixture was stirred for a further 4 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in EtOAc (10ml) and washed with water (3x5ml). The organic layer was dried (MgSO _4), filtered and evaporated in vacuo. Purification by flash column chromatography (eluting with a gradient of 10-100% EtOAc/heptane) gave the title compound (132 mg, 12%) as a yellow oil.

HPLC MS (Method A): [m/z]: 493.15 [M+H] ^+.
Ethyl 2-(2-{[(tert-butoxy)carbonyl]({2-[(4-fluoro-2-nitrophenyl)carbamoyl]ethyl})amino}ethyl)-1,3-thiazole-4-carboxylate (136)

In a similar manner to General Procedure 4, 2-[2-({2-[(4-fluoro-2-nitrophenyl)carbamoyl]ethyl}amino)ethyl]-1 in THF (60 ml) for 16 hours at room temperature. , 3-thiazole-4-carboxylate (133) (2.26 g, 2.145 mmol), Boc ₂ O (1.87 g, 8.58 mmol) and TEA (0.848 ml, 6.43 mmol) by flash column chromatography. After purification by chromatography (eluting with a gradient of 10-100% EtOAc/heptane), the title compound (0.43 g, 38%) was obtained as a yellow oil.

1H-NMR (DMSO-d6, 500MHz): d [ppm] = 10.30 (s, 1H), 8.41 (s, 1H), 7.89 (d, J = 8.5Hz, 1H), 7 .62 (m, 2H), 4.29 (q, J = 7.1Hz, 2H), 3.54 (m, 2H), 3.41 (t, J = 7.1Hz, 2H), 3.22. (T, J=7.0 Hz, 2H), 2.58 (m 2H), 1.35-1.27 (m, 12H)
HPLCMS (Method A): [m/z]: 511.1 [M+H] ^+.
Ethyl 2-(2-{[(tert-butoxy)carbonyl]({3-[(2-nitrophenyl)carbamoyl]propyl})amino}ethyl)-1,3-thiazole-4-carboxylate (137)

In a manner similar to general procedure 4, ethyl 2-[2-({3-[(2-nitrophenyl)carbamoyl]propyl}amino)ethyl]-1,3-thiazole-4-carboxy in THF (50 ml). Rate (134) (3.0 g, 5.32 mmol, 72% purity), Boc ₂ O (2.44 g, 11.17 mmol) and TEA (2.10 ml, 15.96 mmol) were stirred at room temperature for 24 hours. Further Boc ₂ O (2.32 g, 10.64 mmol) and TEA (0.7 ml, 5.32 mmol) were added and the reaction was stirred at room temperature for 96 h upon reverse phase column chromatography (0-100% MeCN/0. After purification by elution with a water gradient), the title compound (0.287g, 10%) was obtained as a yellow oil.

¹ H NMR (DMSO-d6, 500 MHz): d[ppm]=10.23 (s, 1H), 8.40 (s, 1H), 7.93 (dd, J=8.2, 1.4 Hz, 1H), 7.71-7.66 (m, 1H), 7.62 (dd, J=8.1, 1.4Hz, 1H), 7.37-7.32 (m, 1H), 4. 28 (q, J=7.1 Hz, 2H), 3.53 (t, J=6.9 Hz, 2H), 3.25-3.15 (m, 4H), 2.32 (t, J=7). .4 Hz, 2H), 1.81-1.72 (m, 2H), 1.40-1.29 (br m, 9H), 1.28 (t, J=7.1Hz, 3H).
HPLCMS (Method A): [m/z]: 507.1 [M+H] ^+.
Ethyl 2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl][(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate (138)

Ethyl 2-(2-{[(tert-butoxy)carbonyl]({2-[(2-nitrophenyl)carbamoyl]ethyl})amino}ethyl)-1,3-thiazole-4-carboxylate (135)( A suspension of 175 mg, 0.36 mmol) and iron powder (238 mg, 4.26 mmol) in AcOH was heated at 80° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with DCM (10 ml) and neutralized with saturated NaHCO ₃ . The aqueous phase was extracted with DCM (3×10 ml), dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo to give the title compound (121 mg, 76%) as a pale yellow oil.

HPLC MS (Method A): [m/z]: 445.15 [M+H] ^+.
Ethyl 2-(2-{[(tert-butoxy)carbonyl][2-(5-fluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-1,3-thiazole- 4-yl-carboxylate (139)

Ethyl 2-(2-{[(tert-butoxy)carbonyl]({2-[(4-fluoro-2-nitrophenyl)carbamoyl]ethyl})amino}ethyl)-1,3-thiazole-4-carboxylate A suspension of (136) (0.43 g, 0.825 mmol) and iron powder (0.533 g, 9.905 mmol) in AcOH (40 ml) was heated at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and saturated Na ₂ CO ₃ was slowly added to neutralize. The mixture was extracted with DCM (4×40 ml) and the combined organic extracts dried (MgSO ₄ ), filtered and evaporated in vacuo to give the title compound as an off-white glassy solid (0.445 g, quant). Was obtained.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.34 (s, 1H), 8.40 (s, 1H), 7.27 (s, 2H), 6.96 (s, 1H). ), 4.28 (q, J=7.1 Hz, 2H), 3.59 (t, J=7.1 Hz, 2H), 3.55 (br s, 2H), 3.22 (br s, 2H). ), 3.00 (br s, 2H), 1.34-1.20 (m, 12H)
HPLC MS (method A): [m/z]: 463.1 [M+H] ^+.
Ethyl 2-(2-{[3-(1H-1,3-benzodiazol-2-yl)propyl][(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate (140)

Iron powder (0.368 g, 6.595 mmol) was taken from ethyl 2-(2-{[(tert-butoxy)carbonyl]({3-[(2-nitrophenyl)carbamoyl]propyl})amino in AcOH (10 ml). } Ethyl)-1,3-thiazole-4-carboxylate (137) (0.287 g, 0.55 mmol, purity 97%). The reaction was stirred at 80° C. for 1 hour. The reaction was allowed to cool to room temperature. Water (50 ml) was added followed by Na ₂ CO ₃ until pH ˜9. The aqueous layer was extracted with DCM (4 x 50 ml). The combined organic layers were dried (MgSO _4), filtered, and evaporation of the solvent, the title compound (0.291 g, quantitative) as a pale orange oil.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.15 (s, 1H), 8.39 (s, 1H), 7.53-7.47 (m, 1H), 7.43. -7.35 (m, 1H), 7.14-7.06 (m, 2H), 4.28 (q, J=7.1Hz, 2H), 3.58-3.51 (m, 2H) , 3.26-3.21 (m, 4H), 2.77 (t, J=7.6Hz, 2H), 2.01-1.91 (m, 2H), 1.30 (s, 9H). , 1.28 (t, J=7.1Hz, 3H)
HPLC MS (Method A): [m/z]: 459.1 [M+H] ^+.
2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl][(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate( 141)

In a manner similar to general procedure 5, ethyl 2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl][(tert- Butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate (138) (156 mg, 0.35 mmol) and LiOH (33 mg, 1.35 mmol) acidified with AcOH, 3:1 THF/EtOAc. After extraction with (3×10 ml), drying (MgSO ₄ ), filtration and evaporation in vacuo, the title compound (100 mg, 68%) was obtained as a tan solid.

HPLC MS (Method A): [m/z]: 417.1 [M+H] ^+.
2-(2-{[(tert-butoxy)carbonyl][2-(5-fluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-1,3-thiazole-4 -Carboxylic acid (142)

In a manner similar to General Procedure 5, ethyl 2-(2-{[(tert-butoxy)carbonyl][2-(5-fluoro-1H-1,3-benzodi) in THF/water (45 ml/15 ml). Azol-2-yl)ethyl]amino}ethyl)-1,3-thiazol-4-carboxylate (139) (380 mg, 0.83 mmol) and LiOH (59 mg, 2.48 mmol) gave the title compound (319 mg, 82). %, purity 92%) was obtained as a white solid.

HPLCMS (Method A): [m/z]: 435.05 [M+H] ⁺
2-(2-{[3-(1H-1,3-benzodiazol-2-yl)propyl][(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylic acid ( 143)

In a manner similar to General Procedure 5, ethyl 2-(2-{[3-(1H-1,3-benzodiazol-2-yl)propyl in THF/water (25 ml/10 ml) at room temperature for 24 hours. ] [(Tert-Butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate (140) (291 mg, 0.550 mmol, purity 87%) and LiOH (39 mg, 1.649 mmol). The compound (219 mg, 72%) was obtained as a glassy solid.

1H-NMR (Acetone-d _6, 500 MHz): d [ppm]=7.87 (s, 1H), 7.06-6.96 (m, 2H), 6.70-6.63 (m, 2H). ), 3.90-3.85(m, 2H), 3.10(t, J=6.8Hz, 2H), 2.76(t, J=7.0Hz, 2H), 2.34(t). , J=7.4 Hz, 2H), 1.57-1.49 (m, 2H), 0.85 (s, 9H).
HPLCMS (Method A): [m/z]: 431.1 [M+H] ^+.
tert-Butyl N-[2-(1H-1,3-benzodiazol-2-yl)ethyl]-N-[2-(4-{[(3,5-difluoropyridin-2-yl)methyl]] Carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (144)

In a manner similar to general procedure 6, 2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl][(tert-butoxy)carbonyl]amino in DMF (3 ml). } Ethyl)-1,3-thiazole 4-carboxylic acid (141) (100 mg, 0.24 mmol), (3,5-difluoropyridin-2-yl)methanamine dihydrochloride (78 mg, 0.36 mmol), DIPEA( After purification by basic preparative HPLC with 0.21 ml, 1.2 mmol) and HATU (137 mg, 0.36 mmol), the title compound (77 mg, 59%) was obtained as a white solid.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.30 (br s, 1H), 8.09 (s, 1H), 7.55 (br s, 1H), 7.48 (s). , 2H), 7.20 (d, J=3.3 Hz, 2H), 4.82 (s, 2H), 4.73 (s, 2H), 3.70 (m, 4H), 3.08 ( m, 2H), 1.16 (s, 9H)
HPLC MS (Method A): [m/z]: 543.15 [M+H] ^+.
tert-butyl N-[2-(5-fluoro-1H-1,3-benzodiazol-2-yl)ethyl]-N-[2-(4-{[(3-fluoropyridin-2-yl) Methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (145)

In a similar manner to General Procedure 6, 2-(2-{[(tert-butoxy)carbonyl][2-(5-fluoro-1H-1,3-benzodiazol-2-yl) in DMF (4 ml). ) Ethyl]amino}ethyl)-1,3-thiazole-4-carboxylic acid (142) (160 mg, 0.34 mmol, 92% purity), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2). (101 mg, 0.51 mmol), DIPEA (0.18 ml, 1.01 mmol) and HATU (192 mg, 0.51 mmol) after purification by flash column chromatography (eluting with a gradient of 0-50% MeOH/EtOAc). The title compound (112 mg, 61%) was obtained as a white solid.

1H-NMR (DMSO-d6,500MHz): d[ppm]=12.33 (br s, 1H), 8.66 (br s, 1H), 8.36 (br s, 1H), 8.17 ( brs, 1H), 7.72-7.66 (m, 1H), 7.53-7.36 (m, 2H), 7.33-7.21 (m, 1H), 7.00-6. .91 (m, 1H), 4.66 (d, J = 4.5Hz, 2H), 3.63 (t, J = 7.0Hz, 2H), 3.58 (t, J = 6.9Hz, 2H), 3.24 (t, J=6.9 Hz, 2H), 3.02 (m, 2H), 1.35-1.18 (m, 9H)
HPLC MS (Method A): [m/z]: 543.1 [M+H] ^+.
tert-Butyl N-[2-(4-{[(3,5-difluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]-N-[2-(5 -Fluoro-1H-1,3-benzodiazol-2-yl)ethyl]carbamate (146)

In a similar manner to General Procedure 6, 2-(2-{[(tert-butoxy)carbonyl][2-(5-fluoro-1H-1,3-benzodiazol-2-yl) in DMF (3 ml). ) Ethyl]amino}ethyl)-1,3-thiazole-4-carboxylic acid (142) (12 mg, 0.28 mmol), (3,5-difluoropyridin-2-yl)methanamine dihydrochloride (90 mg, 0. 41 mmol), DIPEA (0.24 ml, 1.38 mmol) and HATU (158 mg, 0.41 mmol) gave the title compound (72 mg, 47%) as a colorless glassy solid after purification by basic preparative HPLC. .

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.33 (br s, 1H), 8.68 (br s, 1H), 8.44 (br s, 1H), 8.16 ( br s,1H), 7.90 (d, J=11.0 Hz, 1H), 7.27 (br s, 2H), 6.96 (br s, 1H), 4.62 (d, J=5) 0.7 Hz, 2H), 3.65-3.57 (m, 4H), 3.22 (m, 2H), 3.01 (br s, 2H), 1.24 (m, 9H).
HPLCMS (Method A): [m/z]: 561.15 [M+H] ^+.
tert-butyl N-[3-(1H-1,3-benzodiazol-2-yl)propyl]-N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl} -1,3-Thiazol-2-yl)ethyl]carbamate (147)

In a similar manner to general procedure 6 for 2 hours at room temperature in 2-(2-{[3-(1H-1,3-benzodiazol-2-yl)propyl][(tert- Butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylic acid (143) (219 mg, 0.39 mmol, purity 78%), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) ) (118 mg, 0.59 mmol), DIPEA (0.346 ml, 1.98 mmol) and HATU (226 mg, 0.59 mmol) after purification by basic preparative HPLC, the title compound (111 mg, 52%) was a colorless oil. Was obtained as.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.15 (s, 1H), 8.66 (br s, 1H), 8.36 (d, J=4.3 Hz, 1H), 8.16 (s, 1H), 7.73-7.63 (m, 1H), 7.52-7.45 (m, 1H), 7.45-7.34 (m, 2H), 7. 18-7.01 (m, 2H), 4.65 (d, J=5.5Hz, 2H), 3.59 (t, J=7.0Hz, 2H), 3.29-3.23 (m , 4H), 2.78 (t, J=7.5 Hz, 2H), 2.05-1.92 (m, 2H), 1.30 (s, 9H).
HPLC MS (Method A): [m/z]: 539.15 [M+H] ^+.
2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3,5-difluoropyridin-2-yl)methyl]-1 ,3-thiazole-4-carboxamide trihydrochloride (Example compound No. 116)

In a similar manner to General Procedure 2, 5 hours at room temperature and 20 hours at 40° C., 12M HCl in MeOH (3 ml) (0.378 ml, 4.541 mmol) and tert-butyl N-[2-(1H-1. ,3-Benzodiazol-2-yl)ethyl]-N-[2-(4-{[(3,5-difluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl ) Ethyl]carbamate (144) (77 mg, 0.142 mmol) gave the title compound (60 mg, 73%) as a yellow solid.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.29 (d, J=2.3Hz, 1H), 8.23 (s, 1H), 7.79 (dd, J=6. 1, 3.2 Hz, 2H), 7.64-7.59 (m, 3H), 4.77 (s, 2H), 3.78 (s, 4H), 3.72 (t, J=6. 4Hz, 2H), 3.59 (d, J=5.9Hz, 2H)
HPLC MS (method D): [m/z]: 443.1 [M+H] ^+.
2-(2-{[2-(5-fluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl] -1,3-thiazole-4-carboxamide trihydrochloride (Example compound No. 120)

In a similar manner to General Procedure 2 for 16 hours at room temperature, 12 M HCl in MeOH (4 ml) (0.344 ml, 4.128 mmol) and N-[2-(5-fluoro-1H-1,3-benzodi). Azol-2-yl)ethyl]-N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (145) (112 mg, 0.206 mmol) followed by 12M HCl (0.344 ml, 4.128 mmol) at room temperature for a further 20 hours and 40° C. for 3 hours to give the title compound (80 mg, 67%) as a white solid. ..

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.57(d, J=5.4Hz, 1H), 8.28(t, J=8.8Hz, 1H), 8.25( s, 1H), 7.89 (dt, J=9.5, 5.0 Hz, 1H), 7.81 (dd, J=9.0, 4.3 Hz, 1H), 7.58 (dd, J =8.1, 2.3 Hz, 1H), 7.42 (td, J=9.3, 2.4 Hz, 1H), 4.97 (s, 2H), 3.85-3.79 (m, 4H), 3.75 (t, J=6.3Hz, 2H), 3.62 (t, J=6.3Hz, 2H)
HPLC MS (Method D): [m/z]: 443.2 [M+H] ^+.
N-[(3,5-difluoropyridin-2-yl)methyl]-2-(2-{[2-(5-fluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino} Ethyl)-1,3-thiazole-4-carboxamide trihydrochloride (Example compound No. 123)

In a similar manner to General Procedure 2 for 16 hours at room temperature, 12M HCl in MeOH (3 ml) (0.257 ml, 3.08 mmol) and tert-butyl N-[2-(4-{[(3,5- Difluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]-N-[2-(5-fluoro-1H-1,3-benzodiazol-2-yl)ethyl Carbamate (146) (72 mg, 0.128 mmol) was added followed by further 12M HCl (0.257 ml, 3.08 mmol) and the mixture was stirred at 45° C. for 4 h, the title compound (28 mg, 38%) was white. Obtained as a solid.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.28(d, J=2.3Hz, 1H), 8.23(s, 1H), 7.79(dd, J=9. 0, 4.3 Hz, 1H), 7.60 (m, 1H), 7.56 (dd, J=8.1, 2.3 Hz, 1H), 7.40 (td, J=9.3, 2) .4 Hz, 1 H), 4.76 (s, 2 H), 3.77 (m, 4 H), 3.73 (t, J=6.4 Hz, 2 H), 3.60 (t, J=6.4 Hz) , 2H)
HPLCMS (Method D): [m/z]: 461.2 [M+H] ^+.
2-(2-{[3-(1H-1,3-benzodiazol-2-yl)propyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3 -Thiazole-4-carboxamide trihydrochloride (Example compound No. 125)

In a similar manner to General Procedure 2 for 16 hours at 40° C., 12M HCl (0.405 ml, 4.864 mmol) in MeOH (3 ml) and tert-butyl N-[3-(1H-1,3-benzodiene. Azol-2-yl)propyl]-N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (147) (131 mg, 0.243 mmol) gave the title compound (48 mg, 35%) as a white solid.

1H-NMR (Methanol-d4,500MHz): d [ppm] = 8.48 (d, J = 5.1Hz, 1H), 8.23 (s, 1H), 8.07-8.00 (m, 1H), 7.80-7.76 (m, 2H), 7.74-7.66 (m, 1H), 7.63-7.58 (m, 2H), 4.91 (s, 2H). , 3.65 (t, J=6.4 Hz, 2H), 3.57 (t, J=6.6 Hz, 2H), 3.41-3.32 (m, 4H), 2.49-2. 40 (m, 2H)
HPLC MS (Method D): [m/z]: 439.2 [M+H] ^+.
General Procedure 11: tert-Butyl 3-carbamothioylpyrrolidine-1-carboxylate (148)

Lawesson's reagent (0.42 g, 1.03 mmol) was added in one portion to tert-butyl 3-carbamoylpyrrolidine-1-carboxylate (0.4 g, 1.87 mmol) in DCM (5 ml) and the reaction was at room temperature. Stir for 2 hours. The reaction mixture was loaded directly onto silica and purified by flash column chromatography (eluting with a gradient of 0-100% EtOAc/heptane) to give the title compound (0.36 g, 79%) as an off-white solid.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=7.46 (d, J=8.6 Hz, 1H), 7.01 (br s, 1H), 3.75-3.66 (m, 1H), 3.65-3.54 (m, 1H), 3.59 (dd, 11 and 8.1 Hz, 1H), 3.37 (q, J=8.7 Hz, 1H), 3.27 ( p, J=7.8 Hz, 1H), 2.24-2.12 (m, 3H), 1.46 (s, 9H).
HPLC MS (Method A): [m/z]: 252.95 [M+Na] ^+.
Ethyl 2-{1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl}-1,3-thiazol-4-carboxylate (149)

In a manner similar to general procedure 1 for 21 hours at room temperature ethyl 3-bromo-2-oxopropanoate (2.5 ml, 19.75 mmol) in EtOH (50 ml), tert-butyl 3-carbamothioylpyrrolidine. 1-carboxylate (148) (3.96g, 17.19mmol) and CaCO ₃ (0.87 g, 8.73 mmol) by purification by flash column chromatography (eluting with a gradient of 0 to 70% EtOAc / heptane) Afterwards, the title compound (2.84 g, 51.9%) was obtained as a yellow oil which solidified on standing.

1H-NMR (CDCl ₃ , 250 MHz): d [ppm] = 8.08 (s, 1H), 4.41 (q, J = 7.1 Hz, 2H), 3.96-3.76 (m, 2H). ), 3.73-3.51 (m, 2H), 3.51-3.35 (m, 1H), 2.35-2.44 (m, 1H), 2.28-2.14 (m. , 1H), 1.46(s, 9H), 1.39(t, J=7.1Hz, 3H)
HPLC MS (Method A): [m/z]: 349.05 [M+Na] ^+.
2-{1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl}-1,3-thiazole-4-carboxylic acid (150)

In a manner similar to general procedure 5, LiOH (1.04 g, 43.5 mmol) and ethyl 2-{1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl in THF (30 ml)/water (30 ml). }-1,3-Thiazol-4-carboxylate (149) (2.84 g, 8.7 mmol) gave the title compound (2.48 g, 93.6%) as a yellow solid. The compound was used in the next step without further purification.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=12.94 (s, 1H), 8.37 (s, 1H), 3.94-3.78 (m, 1H), 3.78. -3.68 (m, 1H), 3.49-3.39 (m, 2H), 2.44-2.24 (m, 1H), 2.19-1.98 (m, 1H), 1 .41 (s, 9H). CH signal obscured by H ₂ O peak HPLC MS (Method A): [m/z]: 321.05 [M+Na] ⁺ and 297.1 [M+H] ^+.
tert-Butyl 3-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)pyrrolidine-1-carboxylate (151)

2-{1-[(tert-Butoxy)carbonyl]pyrrolidin-3-yl}-1,3-thiazol-4-carboxylic acid (150) in DMF (14 ml) in a similar manner using general procedure 6. (1 g, 3.35 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (1 g, 5.03 mmol), DIPEA (1.93 ml, 11.06 mmol), HATU (1.9 g, 5.03 mmol) by flash column chromatography (eluting with a gradient of 0-100% EtOAc/heptane) followed by repurification by flash column chromatography (eluting with a gradient of 0-10% MeOH/DCM). The title compound (1.27 g, 86%) was obtained as a yellow oil.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.71 (t, J=5.6 Hz, 1H), 8.38 (dt, J=4.7, 1.4 Hz, 1H), 8.20 (s, 1H), 7.70 (ddd, J=10.2, 8.3, 1.3 Hz, 1H), 7.40 (dt, J=8.5, 4.4 Hz, 1H) , 4.66 (dd, J=5.7, 1.5 Hz, 2H), 3.94-3.81 (m, 1H), 3.82-3.66 (m, 1H), 3.58-. 3.40 (m, 2H), 2.43-2.26 (m, 1H), 2.25-2.04 (m, 1H), 1.40 (s, 9H). CH signal obscured by H ₂ O peak HPLC MS (Method A): [m/z]: 407.1 [M+H] ^+.
tert-Butyl 3-{4-[(pyridin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}pyrrolidin-1-carboxylate (152)

In a similar manner using general procedure 6 2-{1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl}-1,3-thiazol-4-carboxylic acid (150) in DMF (14 ml). Flash column with (1 g, 3.35 mmol), pyridin-2-ylmethanamine (0.52 ml, 5.03 mmol), DIPEA (1.17 ml, 6.7 mmol) and HATU (1.9 g, 5.03 mmol). After purification by chromatography (eluting with a gradient of 0-100% EtOAc/heptane), the title compound (1.54 g, 100%) was obtained as a yellow solid.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.90 (s, 1H), 8.52 (d, J=4.0 Hz, 1H), 8.22 (s, 1H), 7 .76 (td, J=7.7, 1.8 Hz, 1H), 7.36-7.21 (m, 2H), 4.58 (d, J=6.0 Hz, 2H), 3.92- 3.82 (m, 1H), 3.84-3.71 (m, 1H), 3.68-3.42 (m, 3H), 2.34-2.25 (m, 1H), 2. 27-2.11 (m, 1H)
HPLCMS (Method A): [m/z]: 389.15 [M+H] ^+.
N-[(3-fluoropyridin-2-yl)methyl]-2-(pyrrolidin-3-yl)-1,3-thiazol-4-carboxamide dihydrochloride (153)

In a similar manner using General Procedure 2 at 40° C. for 4 h, 12 M HCl (6 ml) in MeOH (25 ml) and tert-butyl 3-(4-{[(3-fluoropyridin-2-yl)methyl. ] Carbamoyl}-1,3-thiazol-2-yl)pyrrolidine-1-carboxylate (151) (1.27 g, 2.87 mmol) gave the title compound (1.11 g, 96.7%) a cream foam. Was obtained as. The compound was used in the next step without further purification.

1H-NMR (Methanol-d4, 250MHz): d [ppm] = 8.58 (dd, J = 5.4, 1.2Hz, 1H), 8.28-8.18 (m, 2H), 7. 87 (dt, J=8.6, 4.8 Hz, 1H), 4.94 (d, J=1.3 Hz, 2H), 4.25-4.11 (m, 1H), 3.82 (dd , J=11.8, 4.6 Hz, 1H), 3.72-3.43 (m, 3H), 2.67-2.46 (m, 1H), 2.39-2.23 (m, 1H)
HPLC MS (Method A): [m/z]: 307.05 [M+H] ^+.
N-(pyridin-2-ylmethyl)-2-(pyrrolidin-3-yl)-1,3-thiazol-4-carboxamide dihydrochloride (154)

In a similar manner using General Procedure 2 at 40° C. for 4 hours, 12 M HCl (7 ml) in MeOH (30 ml) and tert-butyl 3-{4-[(pyridin-2-ylmethyl)carbamoyl]-1, 3-Thiazol-2-yl}pyrrolidin-1-carboxylate (152) (1.54 g, 3.35 mmol) gave the title compound (1.42 g, 99%) as a pale brown foam. The compound was used in the next step without further purification.

1H-NMR (Methanol-d4, 250MHz): d[ppm]=8.77(d, J=5.9Hz, 1H), 8.65-8.54(m, 1H), 8.25(s, 1H), 8.12 (d, J=8.1 Hz, 1H), 7.99 (t, J=6.8 Hz, 1H), 4.96 (s, 2H), 4.17 (ddd, J= 11.5, 7.3, 4.3 Hz, 1H), 3.86 (dd, J=11.9, 4.2 Hz, 1H), 3.79-3.41 (m, 3H), 2.56 (Dq, J=13.4, 8.3 Hz, 1H), 2.41-2.21 (m, 1H)
HPLCMS (Method A): [m/z]: 289.05 [MH] ^+.
N-[(3-fluoropyridin-2-yl)methyl]-2-(1-{2-[(2-nitrophenyl)carbamoyl]ethyl}pyrrolidin-3-yl)-1,3-thiazol-4- Carboxamide (155)

In a similar manner to general procedure 8 for 19 h at room temperature in N-[(3-fluoropyridin-2-yl)methyl]-2-(pyrrolidin-3-yl)-1,3- in MeCN (20 ml). Thiazole-4-carboxamide dihydrochloride (153) (1.11 g, 2.78 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (0.59 g, 3.06 mmol), DBU(1 After workup with 0.41 ml, 9.45 mmol, the title compound (1.53 g, 99%) was obtained as a yellow oil.

1H-NMR (DMSO-d6, 500MHz): d[ppm] = 10.69 (s, 1H), 8.67 (t, J = 5.7Hz, 1H), 8.38 (dt, J = 4. 6,1.4 Hz, 1H), 8.11 (s, 1H), 7.96 (dd, J=8.2, 1.5 Hz, 1H), 7.79 (dd, J=8.2, 1) .2 Hz, 1H), 7.73-7.67 (m, 2H), 7.40 (dt, J=8.6, 4.4 Hz, 1H), 7.33 (ddd, J=8.5). 7.4, 1.4 Hz, 1H), 4.63 (d, J=4.6 Hz, 2H), 3.87-3.77 (m, 1H), 2.99 (dd, J=9.2). , 7.4 Hz, 1 H), 2.88-2.74 (m, 4 H), 2.70-2.62 (m, 1 H), 2.57 (td, J=6.7, 1.9 Hz, 2H), 2.43-2.34 (m, 1H), 2.08-1.99 (m, 1H)
HPLCMS (Method A): [m/z]: 499.1 [M+H] ^+.
tert-Butyl 3-{4-[(pyridin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}pyrrolidin-1-carboxylate (Example compound No. 214)

In a similar manner to general procedure 8 for 2 hours at 80° C., N-[(3-fluoropyridin-2-yl)methyl]-2-(1-{2-[(2-nitrophenyl)carbamoyl]ethyl. } Pyrrolidin-3-yl)-1,3-thiazol-4-carboxamide (155) (1.53 g, 2.78 mmol), AcOH (15 ml) and iron powder (0.62 g, 11.11 mmol) to give the title compound ( 94 mg, 8%) was obtained as a light brown solid and after purification by flash column chromatography (KP-NH, eluting with 0-25% MeOH/DCM grade) a residue (207 mg) was obtained which was flash column. Repurified by chromatography (KP-NH, eluting with a gradient of 0-3% MeOH/DCM).

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.33(d, J=4.7Hz, 1H), 7.94(s, 1H), 7.58(app t, J=9). .1 Hz, 1 H), 7.47 (br s, 2 H), 7.40-7.32 (m, 1 H), 7.24-7.16 (m, 2 H), 4.75 (d, J= 1.4 Hz, 2H), 3.87-3.80 (m, 1H), 3.17-3.11 (m, 2H), 3.11-2.96 (m, 5H), 2.78-. 2.69 (m, 1H), 2.48-2.38 (m, 1H), 2.18-2.04 (m, 1H)
HPLCMS (Method C): [m/z]: 451.1 [M+H] ^+.
2-(1-{2-[(2-nitrophenyl)carbamoyl]ethyl}pyrrolidin-3-yl)-N-(pyridin-2-ylmethyl)-1,3-thiazole-4-carboxamide (156)

In a similar manner to general procedure 8 for 19 hours at room temperature DBU (1.52 ml, 10.19 mmol) in MeCN (25 ml), N-(pyridin-2-ylmethyl)-2-(pyrrolidin-3-yl). -1,3-Thiazole-4-carboxamide dihydrochloride (154) (84.6%, 1.28 g, 3.0 mmol) and N-(2-nitrophenyl)prop-2-enamide (D) (0. After purification by flash column chromatography (eluting with a gradient of 0-12% MeOH/DCM) by 63 g, 3.3 mmol) the title compound (1.43 g, 99%) was obtained as a yellow oil.

¹ H NMR (DMSO-d6, 500 MHz): d [ppm] = 10.67 (s, 1 H), 8.83 (t, J = 6.0 Hz, 1 H), 8.51 (d, J = 4. 2Hz, 1H), 8.12 (s, 1H), 7.96 (dd, J=8.2, 1.4Hz, 1H), 7.82 (d, J=8.2Hz, 1H), 7. 74 (td, J=7.7, 1.8 Hz, 1H), 7.69 (td, J=8.5, 8.0, 1.5 Hz, 1H), 7.36-7.24 (m, 3H), 4.55 (d, J=6.1 Hz, 2H), 3.87-3.78 (m, 1H), 3.04-2.98 (m, 1H), 2.89-2. 74 (m, 4H), 2.71-2.65 (m, 1H), 2.57 (td, J=6.7, 1.7Hz, 2H), 2.44-2.33 (m, 1H). ), 2.09-2.01 (m, 1H)
HPLCMS (Method A): [m/z]: 481.35 [M+H] ^+.
2-{1-[2-(1H-1,3-benzodiazol-2-yl)ethyl]pyrrolidin-3-yl}-N-(pyridin-2-ylmethyl)-1,3-thiazole-4- Carboxamide (Example compound 215)

In a similar manner to General Procedure 8, 2-(1-{2-[(2-nitrophenyl)carbamoyl]ethyl}pyrrolidin-3-yl)-N-( in AcOH (15 ml) for 2 hours at 80°C. Pyridin-2-ylmethyl)-1,3-thiazole-4-carboxamide (156) (1.43 g, 2.77 mmol) and iron powder (0.62 g, 11.07 mmol) by flash column chromatography (x3). After purification by (eluting with a gradient of 0-40% MeOH/DCM followed by a gradient of 0-3% MeOH/DCM then 0-10% MeOH/DCM), the title compound (116 mg, 10%) is off-white. Obtained as a solid.

1H-NMR (Methanol-d4,500MHz) d[ppm]=8.48 (d, J=4.4Hz, 1H), 7.95(s, 1H), 7.79(app t, J=7. 1 Hz, 1 H), 7.48 (s, 2 H), 7.39 (d, J=7.8 Hz, 1 H), 7.36-7.26 (m, 1 H), 7.25-7.12 ( m, 2H), 4.67 (s, 2H), 3.89-3.78 (m, 1H), 3.18-3.11 (m, 2H), 3.11-2.96 (m, 5H), 2.73 (q, J=8.6Hz, 1H), 2.49-2.39 (m, 1H), 2.19-2.06 (m, 1H).
HPLC MS (Method C): [m/z]: 433.1 [M+H] ^+.
General Scheme 9 above:
General Procedure 12: tert-Butyl 3-carbamoylazetidine-1-carboxylate (157)

1-[(tert-Butoxy)carbonyl]azetidine-3-carboxylic acid (4.96 g, 24.65 mmol) and TEA (5.84 ml, 42.0 mmol) were dissolved in THF (60 ml) and cooled to -20°C. did. Isobutyl chloroformate (4.8 ml, 37.0 mmol) was added slowly and the reaction mixture was stirred below −10° C. for 15 minutes. 28% aqueous ammonia (7.46 ml, 394 mmol) was added, the mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was quenched with saturated NaHCO ₃ (aq), and extracted with DCM (3 × 100ml). Dry the organic extracts combined _(Na 2 _SO 4), filtered and evaporated in vacuo. Purification by flash chromatography using 20-100% EtOAc/heptane followed by a gradient elution of 1-4% MeOH/EtOAc provided the title compound (3.99 g, 81%) as a white solid.

1H-NMR (CDCl ₃ , 250 MHz): d [ppm] = 5.47 (s, 2H), 4.22-4. 01 (m, 4H), 3.34-3.15 (m, 1H), 1.46 (s, 9H)
HPLC MS (Method A): [m/z]: 222.95 [M+Na] ^+.
tert-Butyl 3-carbamoyl-3-methylazetidine-1-carboxylate (158)

In a similar manner to general procedure 12 1-[(tert-butoxy)carbonyl]-3-methylazetidine-3-carboxylic acid (110 mg, 0.51 mmol) in THF (10 ml), TEA (90 mg, 0. 87 mmol), isobutyl chloroformate (0.1 ml, 0.77 mmol) and _NH 3 (28% aqueous solution, 0.15 ml, by 10 mmol), the title compound (102mg, 93%) as a white solid.

1H-NMR (CDCl ₃ , 500 MHz): d [ppm] = 5.63 (s, 1H), 5.37 (s, 1H), 4.21 (d, J = 8.4 Hz, 2H), 3. 72 (d, J=8.4 Hz, 2H), 1.58 (s, 3H), 1.47 (s, 9H)
HPLC MS (Method A): [m/z]: 237 [M+Na] ^+.
tert-Butyl 3-carbamothioylazetidine-1-carboxylate (159)

In a similar manner to General Procedure 11 Lawesson's reagent (4.43 g, 11.0 mmol) in DCM (60 ml) at room temperature for 30 min, tert-butyl 3-carbamoylazetidine-1-carboxylate (157) (3). 0.99 g, 19.9 mmol) was run through a silica plug with a gradient elution of 10-80% EtOAc/heptane to give the title compound (4.47 g) as a pale yellow residue.

HPLC MS (Method A): [m/z]: 238.9 [M+Na] ^+.
tert-Butyl 3-carbamothiyl-3-methylazetidine-1-carboxylate (160)

In a manner similar to general procedure 11, tert-butyl 3-carbamoyl-3-methylazetidine-1-carboxylate (158) (1.0 g, 4.67 mmol) and Lawesson's reagent (1. 04 g, 3.0 mmol) afforded the title compound (1.07 g) as a white solid.

1H-NMR (CDCl ₃ , 250 MHz): d[ppm]=7.47 (s, 1H), 6.88 (s, 1H), 4.33 (d, J=8.3 Hz, 2H), 3. 81 (d, J=8.3 Hz, 2H), 1.72 (s, 3H), 1.47 (s, 9H)
HPLCMS (Method A): [m/z]: 253.05 [M+Na] ^+.
Ethyl 2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-thiazol-4-carboxylate (161)

In a manner similar to General Procedure 1 tert-butyl 3-carbamothioylazetidine-1-carboxylate (159) (4.47 g, 20.67 mmol) in EtOH (40 ml), ethyl 3-bromo-2-. After purification by flash chromatography with oxopropanoate (2.85 ml, 22.73 mmol) and calcium carbonate (1.12 g, 11.0 mmol) using gradient elution from 10-50% EtOAc/heptane, the title compound ( 3.54 g, 54%) was obtained as a yellow oil.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.49 (s, 1H), 4.37-4.23 (m, 5H), 4.00 (m, 2H), 1.41. (S, 9H), 1.31 (t, J=7.1Hz, 3H)
HPLC MS (Method A): [m/z]: 335 [M+Na] ^+.
Ethyl 2-{1-[(tert-butoxy)carbonyl]-3-methylazetidin-3-yl}-1,3-thiazol-4-carboxylate (162)

In a manner similar to General Procedure 1 tert-butyl 3-carbamothiyl-3-methylazetidine-1-carboxylate (160) (0.82 g, 3.56 mmol) in EtOH (20 ml), ethyl 3-bromo-. 2-oxopropanoate (0.49 ml, 4.0 mmol) and calcium carbonate (0.2 g, 2.0 mmol) gave the title compound (1.0 g) as a pale yellow oil.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.14 (s, 1H), 4.44 (q, J=7.1 Hz, 2H), 4.39 (d, J=8.0 Hz). , 2H), 3.98 (d, J=8.0 Hz, 2H), 1.83 (s, 3H), 1.48 (s, 9H), 1.43 (t, J=7.1 Hz, 3H). )
HPLC MS (Method A): [m/z]: 349.15 [M+Na] ^+.
2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-thiazole-4-carboxylic acid (163)

In a manner similar to general procedure 5 ethyl 2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-thiazol-4-carboxy in THF (40 ml) and water (40 ml). Rate (161) (2.52 g, 7.91 mmol) and LiOH (0.57 g, 23.72 mmol) gave the title compound (2.23 g, purity 87%, 86%) as an orange solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=13.03 (s, 1H), 8.40 (s, 1H), 4.31-4.23 (m, 2H), 4.23. -4.17 (m, 1H), 4.05-3.93 (m, 2H), 1.40 (s, 9H)
HPLC MS (Method A): [m/z]: 306.85 [M+Na] ^+.
2-{1-[(tert-Butoxy)carbonyl]-3-methylazetidin-3-yl}-1,3-thiazole-4-carboxylic acid (164)

In a manner similar to General Procedure 5, ethyl 2-{1-[(tert-butoxy)carbonyl]-3-methylazetidin-3-yl}-1,3 in THF (30 ml) and water (15 ml). -Thiazole-4-carboxylate (162) (1.0 g, 3.06 mmol) and LiOH (0.22 g, 10.0 mmol) gave the title compound (853 mg, 93%) as a pale yellow foam.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.44 (s, 1H), 4.16 (d, J=8.2 Hz, 2H), 3.90 (d, J=8. 2Hz, 2H), 1.72 (s, 3H), 1.41 (s, 9H)
HPLCMS (Method A): [m/z]: 321.05 [M+Na] ^+.
tert-Butyl 3-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)azetidine-1-carboxylate (165)

In a similar manner to general procedure 6 2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-thiazol-4-carboxylic acid (163) (87) in DCM (40 ml). %, 2.23 g, 6.69 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (1.6 g, 8.03 mmol), DIPEA (4.66 ml, 26.77 mmol) and HATU. (3.05 g, 8.03 mmol) gives the title compound (2.51 g, 82% purity, 79%) as an orange oil after purification by flash column chromatography using an elution gradient 20-100% EtOAc/heptane. It was

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.79 (t, J=5.7 Hz, 1H), 8.38 (dt, J=4.6, 1.4 Hz, 1H), 8.24 (s, 1H), 7.76-7.62 (m, 1H), 7.46-7.35 (m, 1H), 4.66 (dd, J=5.7, 1.5Hz) , 2H), 4.34-4.17 (m, 3H), 4.16-4.05 (m, 2H), 1.39 (s, 9H).
HPLCMS (Method A): [m/z]: 393 [M+H] ^+.
tert-Butyl 3-[4-({5H,6H,7H-cyclopenta[b]pyridin-7-yl}carbamoyl)-1,3-thiazol-2-yl]azetidine-1-carboxylate (166)

In a similar manner to General Procedure 6 2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-thiazol-4-carboxylic acid (163) (300 mg) in DCM (20 ml). , 1.06 mmol), 5H,6H,7H-cyclopenta[b]pyridin-7-amine dihydrochloride (284 mg, 1.37 mmol), DIPEA (0.61 ml, 3.5 mmol) and HATU (0.52 g, 1). .4 mmol) afforded the crude title compound (1.32 g, purity 30%, 94%) which was used in the next step without purification.

HPLCMS (Method A): [m/z]: 401.1 [M+H] ^+.
tert-Butyl 3-(4-{[(3-chloropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)azetidine-1-carboxylate (167)

In a manner similar to general procedure 6 2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-thiazol-4-carboxylic acid (163) (364 mg) in DCM (20 ml). , 1.28 mmol), (3-chloropyridin-2-yl)methanamine dihydrochloride (359 mg, 1.66 mmol), DIPEA (0.74 ml, 4.2 mmol) and HATU (0.63 g, 1.7 mmol). After purification by flash column chromatography (eluting with a gradient of 0-100% EtOAc/heptane), the title compound (493 mg, 94%) was obtained as a pale yellow oil.

1H-NMR (DMSO-d6, 250MHz): d [ppm] = 8.79 (t, J = 5.5Hz, 1H), 8.51 (dd, J = 4.7, 1.4Hz, 1H), 8.27 (s, 1H), 7.96 (dd, J=8.1, 1.4 Hz, 1H), 7.39 (dd, J=8.1, 4.7 Hz, 1H), 4.70 (D, J=5.5 Hz, 2H), 4.38-4.18 (m, 3H), 4.09 (q, J=3.9 Hz, 2H), 1.41 (s, 9H).
HPLC MS (Method A): [m/z]: 409.05 [M+H] ^+.
tert-Butyl 3-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)-3-methylazetidine-1-carboxylate (168)

2-{1-[(tert-Butoxy)carbonyl]-3-methylazetidin-3-yl}-1,3-thiazol-4-carboxylic acid in DCM (20 ml) in a similar manner to general procedure 6. (164) (546 mg, 1.83 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (400 mg, 2.01 mmol), DIPEA (1.05 ml, 6.0 mmol) and HATU (830 mg). , 2.0 mmol) to give the crude title compound (824 mg) as a pale yellow oil. The crude material was used in the next step without further purification.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.38-8.33 (m, 1H), 8.28 (s, 1H), 8.02 (s, 1H), 7.37-. 7.31 (m, 1H), 7.23-7.17 (m, 1H), 4.81-4.76 (m, 2H), 4.30 (d, J=7.5Hz, 2H), 3.88 (d, J=7.5 Hz, 2H), 1.52 (s, 3H), 1.40 (s, 9H)
HPLCMS (Method A): [m/z]: 407.2 [M+H] ^+.
2-(azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazol-4-carboxamide dihydrochloride (169)

In a similar manner to General Procedure 4, tert-butyl 3-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl) in MeOH (25 ml). Azetidine-1-carboxylate (165) (82%, 2.51 g, 5.26 mmol) and 12M HCl (8.8 ml) gave the title compound (2.26 g, 85% pure, quantitative) as a light brown solid. Was obtained.

1H-NMR (Methanol-d4, 250MHz): d[ppm]=8.56 (d, J=5.2Hz, 1H), 8.27(s, 1H), 8.24-8.07(m, 1H), 7.87-7.73 (m, 1H), 4.96-4.91 (m, 2H), 4.57-4.41 (m, 5H).
HPLC MS (Method A): [m/z]: 292.95 [M+H] ^+.
2-(azetidin-3-yl)-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl}-1,3-thiazol-4-carboxamide (170)

In a manner similar to general procedure 4, crude tert-butyl 3-[4-({5H,6H,7H-cyclopenta[b]pyridin-7-yl}carbamoyl)-1,3-thiazole in MeOH (10 ml). 2-yl]azetidine-1-carboxylate (166) (1.32 g, 30% purity, 1.06 mmol) and 12M HCl (1 ml), purified using SCX-2 cartridge, rinsed with DCM and MeOH. Then, after eluting with 7N ammonia in MeOH, the title compound (322 mg, quantitative) was obtained as a white solid.

HPLCMS (Method A): [m/z]: 300.95 [M+H] ^+.
2-(azetidin-3-yl)-N-[(3-chloropyridin-2-yl)methyl]-1,3-thiazol-4-carboxamide (171)

In a similar manner to general procedure 4, tert-butyl 3-(4-{[(3-chloropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl) in MeOH (30 ml). Azetidine-1-carboxylate (167) (423 mg, 1.03 mmol) and 12M HCl (2 ml), purified with SCX-2 cartridge, rinsed with DCM and MeOH, then eluted with 7N ammonia in MeOH. , The title compound (330 mg, 99%) was obtained as a white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.71 (t, J=5.5 Hz, 1H), 8.52 (dd, J=4.7, 1.4 Hz, 1H), 8.24 (s, 1H), 7.96 (dd, J=8.0, 1.4 Hz, 1H), 7.39 (dd, J=8.0, 4.7 Hz, 1H), 4.70 (D, J=5.5 Hz, 2H), 4.24 (m, 1H), 3.92-3.87 (m, 2H), 3.76-3.73 (m, 2H)
HPLCMS (Method A): [m/z]: 308.95 [M+H] ^+.
N-[(3-fluoropyridin-2-yl)methyl]-2-(3-methylazetidin-3-yl)-1,3-thiazol-4-carboxamide (172)

In a similar manner to general procedure 4, tert-butyl 3-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl) in MeOH (20 ml). Purify with 3-methylazetidine-1-carboxylate (168) (824 mg, 2.03 mmol) and 12M HCl (2 ml) using SCX-2 cartridge, rinse with DCM and MeOH, then 7N in MeOH. After eluting with ammonia, the title compound (476 mg, 74%) was obtained.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.71 (t, J=5.7 Hz, 1H), 8.39 (dt, J=4.6, 1.3 Hz, 1H), 8.21 (s, 1H), 7.71 (ddd, J = 10.0, 8.3, 1.3 Hz, 1H), 7.46-7.36 (m, 1H), 4.68 (m , 2H), 3.85 (d, J=7.5 Hz, 2H), 3.52 (d, J=7.5 Hz, 2H), 1.72 (s, 3H).
HPLC MS (Method A): [m/z]: 307.20 [M+H] ^+.
2-{1-[2-(1H-1,3-benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-[(3-fluoropyridin-2-yl)methyl]-1, 3-thiazole-4-carboxamide (Example compound No. 193)

In a manner similar to General Procedure 8, 2-(azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide in MeCN (30 ml). Dihydrochloride (169) (85%, 2.26 g, 5.26 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (1.21 g, 6.31 mmol) and DBU (2.35 ml). , 15.77 mmol) to give a crude intermediate which was further reacted with iron powder (0.51 g, 9.0 mmol) and AcOH (5 ml) to give the title compound (122 mg after purification by basic preparative HPLC). , 7%) was obtained as a cream solid.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.33 (dt, J=4.7, 1.3Hz, 1H), 8.12 (s, 1H), 7.62-7. 56 (m, 1H), 7.53-7.47 (m, 2H), 7.39-7.34 (m, 1H), 7.22-7.17 (m, 2H), 4.79 ( d, J=1.7 Hz, 2H), 4.11-4.03 (m, 1H), 3.80 (t, J=7.9 Hz, 2H), 3.55-3.50 (m, 2H). ), 3.07-3.02 (m, 2H), 3.01-2.96 (m, 2H)
HPLC MS (Method G): [m/z]: 437 [M+H] ^+.
2-{1-[2-(1H-1,3-benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl }-1,3-Thiazole-4-carboxamide (Example compound 194)

In a manner similar to General Procedure 8, 2-(azetidin-3-yl)-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl}-1,3-thiazole in MeCN (10 ml). By -4-carboxamide (170) (322 mg, 1.07 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (227 mg, 1.18 mmol) and DBU (0.21 ml, 1.4 mmol). A crude intermediate was obtained which was further reacted with iron powder (0.15 g, 2.6 mmol) in AcOH (4 ml) to give the title compound (139 mg, 48%) as white after purification by basic preparative HPLC. Obtained as a solid.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.35(d, J=5.0Hz, 1H), 8.15(s, 1H), 7.78-7.74(m, 1H), 7.50 (br s, 2H), 7.29 (dd, J=7.6, 5.0 Hz, 1H), 7.24-7.18 (m, 2H), 5.58 (t). , J=8.3 Hz, 1H), 4.05 (tt, J=7.9, 6.4 Hz, 1H), 3.77 (t, J=7.9 Hz, 2H), 3.56-3. 49 (m, 2H), 3.11 (ddd, J=16.3, 9.1, 2.8Hz, 1H), 3.05-3.00 (m, 3H), 3.00-2.94. (M, 2H), 2.73 (m, 1H), 2.11 (m, 1H)
HPLC MS (Method C): [m/z]: 445.3 [M+H] ^+.
2-{1-[2-(1H-1,3-benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-[(3-chloropyridin-2-yl)methyl]-1, 3-thiazole-4-carboxamide (Example compound No. 195)

In a manner similar to general procedure 8, 2-(azetidin-3-yl)-N-[(3-chloropyridin-2-yl)methyl]-1,3-thiazol-4-carboxamide in MeCN (10 ml). (171) (330 mg, 1.07 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (226 mg, 1.18 mmol) and the crude intermediate required by DBU (0.21 ml, 1.4 mmol). The product was obtained which was further reacted with iron powder (150 mg, 2.6 mmol) in AcOH (4 ml) by basic preparative HPLC followed by flash column chromatography (gradient 0-12% MeOH/DCM). After purification by elution), the title compound (80 mg, 27%) was obtained as a white solid.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.45 (dd, J=4.7, 1.4Hz, 1H), 8.15 (s, 1H), 7.88 (dd, J=8.1, 1.4Hz, 1H), 7.51(brs, 2H), 7.32(dd, J=8.1, 4.7Hz, 1H), 7.24-7.19( m, 2H), 4.85-4.82 (m, 2H), 4.11 (m, 1H), 3.84 (t, J=7.9Hz, 2H), 3.59-3.53( m, 2H), 3.10-3.05 (m, 2H), 3.03-2.98 (m, 2H).
HPLC MS (Method C): [m/z]: 453.2 [M+H] ^+.
2-{1-[2-(1H-1,3-benzodiazol-2-yl)ethyl]-3-methylazetidin-3-yl}-N-[(3-fluoropyridin-2-yl) Methyl]-1,3-thiazole-4-carboxamide (Example compound No. 212)

In a manner similar to general procedure 8, N-[(3-fluoropyridin-2-yl)methyl]-2-(3-methylazetidin-3-yl)-1,3-thiazole in MeCN (15 ml). Required by 4-carboxamide (172) (476 mg, 1.55 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (328 mg, 1.71 mmol) and DBU (0.26 ml, 2 mmol). A crude intermediate was obtained, which was further reacted with iron powder (350 mg, 10.0 mmol) in AcOH (5 ml). Purification by basic preparative HPLC, followed by flash column chromatography (eluting with a gradient of 0-30% MeOH/DCM) gave the title compound (162 mg, 23%) as a white solid.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.34-8.27(m,1H),8.14(s,1H),7.60(ddd,J=9.7, 8.5, 1.2 Hz, 1H), 7.51 (s, 2H), 7.37-7.32 (m, 1H), 7.24-7.18 (m, 2H), 4.80( d, J=1.3 Hz, 2H), 3.78 (d, J=7.7 Hz, 2H), 3.47 (d, J=7.7 Hz, 2H), 3.10 (t, J=7). .2 Hz, 2 H), 3.00 (t, J=7.2 Hz, 2 H), 1.78 (s, 3 H)
HPLCMS (Method C): [m/z]: 451.1 [M+H] ^+.
General Scheme 10 above:
Methyl 2,2-dimethyl-3-oxopropanoate (173)

Methyl 3-hydroxy-2,2-dimethylpropanoate (1.45ml, 11.35mmol) and TEA (4.75ml, 34.05mmol) in DCM (45ml) and DMSO (8ml, 113.5mmol) in ice cooling. To the (0° C.) solution was added pyridine sulfur trioxide complex (5.42 g, 34.05 mmol). The resulting mixture was stirred at room temperature for 22 hours. The reaction was quenched with saturated NH ₄ Cl (30 ml). The layers were separated and the aqueous layer was extracted with DCM (40ml). The organic layer was washed successively with 2M HCl (2×20 ml) and brine (15 ml), dried (MgSO ₄ ), filtered and evaporated to give the title compound (0.35 g, 99%) as an orange oil. Was given.

1H-NMR (CDCl ₃ , 250 MHz): d[ppm]=9.66 (s, 1H), 5.30 (s, 1H), 3.75 (s, 3H), 1.35 (s, 6H).
Methyl 3-{[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]amino}-2,2-dimethylpropanoate (174)

DIPEA (1.8 ml, 10.32 mmol) in 2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4- in MeOH (20 ml). Carboxamide dihydrochloride (103) (0.97 g, 2.58 mmol) and methyl 2,2-dimethyl-3-oxopropanoate (173) (0.52 g, 3.36 mmol) were added. The reaction was stirred at room temperature for 18 hours. The reaction was cooled to 0° C. and NaBH ₄ (146 mg, 3.87 mmol) was added in small portions. The reaction was warmed to room temperature and stirred for 3.5 hours. The solvent was evaporated and water (10 ml) was added. The aqueous layer was extracted with EtOAc (3 x 20 ml). The combined organic layers were dried (MgSO _4), filtered and evaporated to give an orange oil (1.1 g). Purification by flash column chromatography (eluting with a gradient of 0-15% MeOH/DCM) gave the title compound (0.95 g, 79%) as a pale yellow oil.

1H-NMR (CDCl ₃ , 250 MHz): d[ppm]=8.43-8.38 (m, 2H), 8.02 (s, 1H), 7.45-7.36 (m, 1H), 7.26-7.20 (m, 1H), 4.85 (dd, J=5.3, 1.7 Hz, 2H), 3.63 (s, 3H), 3.20 (t, J=5) .6 Hz, 2H), 3.10 (t, J=5.8 Hz, 2H), 2.79 (s, 2H), 1.22 (s, 6H)
HPLCMS (Method A): [m/z]: 395.05 [M+H] ⁺
3-{[(tert-butoxy)carbonyl][2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]amino}-2 ,2-Dimethylpropanoate (175)

TEA (0.5 ml, 3.62 mmol) was added to methyl 3-{[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazole- in DCM (10 ml). 2-yl)ethyl]amino}-2,2-dimethylpropanoate (174) (0.95 g, 2.41 mmol) was added. The reaction was stirred at room temperature for 5 minutes, di-tert-butyl dicarbonate (0.63 g, 2.9 mmol) in DCM (10 ml) was added dropwise and the reaction was stirred at room temperature for 20 hours. Evaporation of the solvent and purification by flash column chromatography (eluting with a gradient of 0-100% EtOAc/heptane) gave the title compound (0.94g, 90%) as a clear oil.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.42 (d, J=4.3 Hz, 2H), 8.01 (s, 1H), 7.44 to 7.37 (m, 1H). ), 7.26 (m, 1H, unclear due to solvent peak), 4.85 (dd, J=5.1, 1.7 Hz, 2H), 3.70 (s, 3H), 3.55 (t. , J=7.0 Hz, 2H), 3.48 to 3.41 (br m, 2H), 3.31 to 3.14 (m, 2H), 1.45 (s, 9H), 1.19( s, 6H)
HPLCMS (Method A): [m/z]: 495.15 [M+H] ^+.
3-{[(tert-butoxy)carbonyl][2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]amino}-2 ,2-Dimethylpropanoic acid (176)

In a similar manner using General Procedure 5 LiOH (0.27 g, 11.1 mmol) and 3-{[(tert-butoxy)carbonyl][2-( in THF (6 ml)/water (1.5 ml). 4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]amino}-2,2-dimethylpropanoate (175) (0.94 g, 1.85 mmol) gave the title compound (0.91 g, 96%) as an off-white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.41 (s, 1H), 8.63 (s, 1H), 8.39 (s, 1H), 8.17 (s, 1H). ), 7.71 (ddd, J=10.0, 8.3, 1.2 Hz, 1H), 7.41 (dt, J=8.6, 4.4 Hz, 1H), 4.67 (dd, J=5.6, 1.3 Hz, 2H), 3.53 (t, J=7.1 Hz, 2H), 3.38 (s, 2H), 3.23 (t, J=7.1 Hz, 2H). ), 1.34 (s, 9H), 1.07 (s, 6H)
HPLCMS (Method A): [m/z]: 481.15 [M+H] ^+.
tert-Butyl N-{2-[(2-aminophenyl)carbamoyl]-2,2-dimethylethyl}-N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl} -1,3-Thiazol-2-yl)ethyl]carbamate (177)

In a similar manner using general procedure 6 3-{[(tert-butoxy)carbonyl][2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl} in DMF (10 ml). -1,3-Thiazol-2-yl)ethyl]amino}-2,2-dimethylpropanoic acid (176) (0.5 g, 0.98 mmol), benzene-1,2-diamine (0.14 g, 1. 3 mmol), TEA (0.18 ml, 1.3 mmol) and HATU (0.49 g, 1.3 mmol) after purification by flash column chromatography using a gradient of 0-100% EtOAc/heptane. 51 g, 83%) was obtained as a yellow oil.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.84 (s, 1H), 8.61 (s, 1H), 8.37 (d, J=4.5 Hz, 1H), 8 .16 (s, 1H), 7.70 (ddd, J=10.1, 8.3, 1.2 Hz, 1H), 7.41 (dt, J=8.6, 4.4 Hz, 1H), 7.02-6.86 (m, 2H), 6.78-6.68 (m, 1H), 6.57-6.45 (m, 1H), 4.66 (d, J=4.4Hz) , 2H), 3.55 (t, J=6.9 Hz, 2H), 3.50 (s, 2H), 3.24 (t, J=6.9 Hz, 2H), 1.35 (s, 9H). ), 1.21 (s, 6H)
HPLCMS (Method A): [m/z]: 571.2 [M+H] ^+.
tert-butyl N-[2-(1H-1,3-benzodiazol-2-yl)-2-methylpropyl]-N-[2-(4-{[(3-fluoropyridin-2-yl) Methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (178)

Tert-Butyl N-{2-[(2-aminophenyl)carbamoyl]-2,2-dimethylethyl}-N-[2-(4-{[(3-fluoropyridine-2- Il)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (177) (260 mg, 0.415 mmol) was heated to 80°C for 35 minutes. The reaction was cooled, concentrated in vacuo and the residue was partitioned between EtOAc (10 ml) and saturated _K 2 _CO 3 (10ml). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 10 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and evaporated to give a brown oil. Purification by flash column chromatography (KP-NH column eluting with a gradient of 0-100% DCM/heptane) gave the title compound (172 mg, 71%) as a light brown oil.

¹ H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.43 (br s, 1 H), 8.42 (dt, J=4.6 and 1.2 Hz, 2 H), 7.99 (s , 1H), 7.82-7.69 (m, 1H), 7.47-7.42 (m, 1H), 7.40-7.34 (m, 1H), 7.25-7.18. (M, 2H), 4.91 (d, J=4.5 Hz, 2H), 3.75-3.69 (br m, 2H), 3.59-3.39 (br m, 2H), 3 .11 (t, J=6.3 Hz, 2H), 1.59 (s, 9H), 1.45 (s, 6H)
HPLC MS (Method A): [m/z]: 553.2 [M+H] ^+.
2-(2-{[2-(1H-1,3-benzodiazol-2-yl)-2-methylpropyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl] -1,3-thiazole-4-carboxamide (Example compound No. 199)

In a manner similar to General Procedure 2, TFA (2 ml) was added to tert-butyl N-{2-[(2-aminophenyl)carbamoyl]-2,2-dimethylethyl}-N-[ in DCM (2 ml). 2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (178) (172 mg, 0.25 mmol) and added at room temperature. After stirring for 3 h at 37° C., the title compound was purified by an Isolute SCX-2 cartridge eluting with DCM (2 CV), DCM/MeOH (1:1, 1 CV), MeOH (2 CV), then 7M NH _{3 in} MeOH (2 CV). (79 mg, 70%) was obtained as a beige solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.01 (s, 1H), 8.62 (t, J=5.7 Hz, 1H), 8.37 (dt, J=4. 7 and 1.5 Hz, 1H), 8.02 (s, 1H), 7.74-7.63 (m, 1H), 7.53-7.35 (m, 2H), 7.42-7. 38 (m, 1 H), 7.14-7.06 (m, 2H), 4.64 (dd, J=5.6, 1.4 Hz, 2H), 3.11 (t, J=6. 5 Hz, 2H), 2.91-2.87 (m, 4H), 1.39 (s, 6H)
HPLC MS (Method D): [m/z]: 453.2 [M+H] ^+.
2-(1H-1,3-benzodiazol-2-yl)acetic acid (179)

2M NaOH (90.7 ml, 181 mmol) was added to 2-(1H-1,3-benzodiazol-2-yl)acetonitrile (9.5 g, 60.4 mmol). The reaction was heated at 100° C. for 3 hours. The reaction mixture was cooled to room temperature and acidified to pH 5-6 with 4M HCl. The resulting precipitate was filtered, washed with water and dried in vacuo to give the title compound (9.7g, 77%) as a light brown solid.

1H-NMR (DMSO-d6,500MHz): d[ppm]=7.52-7.46 (m, 1H), 7.45-7.39 (m, 1H), 7.17-7.11 ( m, 1H), 7.11-7.06 (m, 1H), 2.47 (s, 2H)
HPLC MS (Method F): [m/z]: 177.0 [M+H] ^+.
Methyl 2-(1H-1,3-benzodiazol-2-yl)acetate (180)

Thionyl chloride (0.7 ml, 9.65 mmol) was added to 2-(1H-1,3-benzodiazol-2-yl)acetic acid (179) (0.7 g, 3.97 mmol) in MeOH (30 ml) in ice. The cold (0°C) suspension was added dropwise. The reaction mixture was warmed to room temperature and stirred for 18 hours. The mixture was poured into saturated NaHCO ₃ (40ml), and extracted with DCM (3 × 20ml). The combined organic layers were washed with brine (30 ml), dried (NaSO ₄ ), filtered and evaporated to give the title compound compound (0.65 g, 86%) as a cream solid.

1H-NMR (CDCl3, 500MHz): d [ppm] = 10.10 (br s, 1H), 7.72 (br s, 1H), 7.46 (br s, 1H), 7.29-7. 23 (m, 2H), 4.09 (s, 2H), 3.82 (s, 3H)
HPLCMS (Method F): [m/z]: 191.2 [M+H] ^+.
tert-Butyl 2-(2-methoxy-2-oxoethyl)-1H-1,3-benzodiazole-1-carboxylate (181)

In a similar manner to General Procedure 4, methyl 2-(1H-1,3-benzodiazol-2-yl)acetate (180) (650 mg, 3.42 mmol) in THF (30 ml) for 18 hours at room temperature, By TEA (0.5 ml, 3.59 mmol), Boc ₂ O (890 mg, 4.11 mmol) and DMAP (84 mg, 0.68 mmol) by flash column chromatography (eluting with a gradient of 0-100% EtOAc/heptane). After purification, the title compound (940 mg, 95%) was obtained as a cream solid.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=7.96-7.90 (m, 1H), 7.74-7.68 (m, 1H), 7.38-7.31 (m , 2H), 4.28 (s, 2H), 3.73 (s, 3H), 1.69 (s, 9H)
HPLCMS (Method A): [m/z]: 291 [M+H] ^+.
tert-Butyl 2-(1,1-difluoro-2-methoxy-2-oxoethyl)-1H-1,3-benzodiazole-1-carboxylate (182)

KHMDS (1.5 g, 7.61 mmol) in THF (15 ml) was cooled to -78 °C. tert-Butyl 2-(2-methoxy-2-oxoethyl)-1H-1,3-benzodiazole-1-carboxylate (181) (0.74 g, 2.54 mmol) was added and the mixture was -78 °C. And stirred for 45 minutes. A combined mixture of 18-crown-6 (2.01 g, 7.61 mmol) and N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (2.2 g, 7.1 mmol) was added. The mixture was stirred at -78°C for 30 minutes. Further KHMDS (0.75 g, 3.76 mmol) was added and stirred for 20 minutes. Further N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (1.1 g, 3.49 mmol) and 18-crown-6 (1 g, 3.78 mmol) were added. The reaction mixture was then allowed to warm slowly to room temperature and stirred for 18 hours to give a 1.6:1 ratio of difluoride:monofluoride product. Saturated NH ₄ Cl (12 ml) was added, followed by water (20 ml). The organic layer and the aqueous layer were separated. The aqueous layer was extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with brine (100ml), dried (NaSO _4), filtered, and evaporated to give a pink semi-solid (3 g). Purification by flash column chromatography (0-50% TBME/heptane, followed by elution with a gradient of 100% TBME) gave the title compound (0.47 g, 48%) as a yellow oil which solidified on standing. ..

_{1H-NMR (CDCl 3, 250MHz} ): d [ppm] = 8.00-7.81 (m, 2H), 7.55-7.34 (m, 2H), 3.91 (s, 3H), 1.70 (s, 9H).
HPLC MS (Method A): [m/z]: 226.9 [M-BOC+H] ^+.
tert-Butyl 2-(1,1-difluoro-2-hydroxy-2-methoxyethyl)-1H-1,3-benzodiazole-1-carboxylate (183)

NaBH ₄ (44 mg, 1.16 mmol) was added to tert-butyl 2-(1,1-difluoro-2-methoxy-2-oxoethyl)-1H-1,3-benzodiazole-1-carboxylate (182)( 295 mg, 0.76 mmol) was added to an ice cold (0° C.) solution in EtOH (3.5 ml). The reaction was stirred at 0° C. for 1.5 hours and quenched by the dropwise addition of 1M HCl (0.5 ml). Water (10 ml) was added and the aqueous layer was extracted with EtOAc (3 x 10 ml). The combined organic layers were dried (NaSO ₄ ), filtered and evaporated to give a white solid (300 mg). Purification by flash column chromatography (eluting with a gradient of 0-40% EtOAc/heptane) gave the title compound (185 mg, 59%) as a white solid.

1H-NMR (CDCl ₃ , 250 MHz): d[ppm]=8.03-7.77 (m, 1H), 7.63-7.31 (m, 3H), 6.17 (dd, J=6). .4, 4.9 Hz, 1H), 3.69 (s, 3H), 1.52 (s, 9H)
HPLC MS (Method A): [m/z]: 329.05 [M+H] ^+.
4-(2-{[2-(1H-1,3-benzodiazol-2-yl)-2,2-difluoroethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl) Methyl]-1,3-thiazole-2-carboxamide (Example compound No. 196)

Tert-Butyl 2-(1,1-difluoro-2-hydroxy-2-methoxyethyl)-1H-1,3-benzodiazole-1-carboxylate (183) (160 mg, 0.1 ml) in anhydrous toluene (3 ml). 4 mmol), 2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide (103) (136 mg, 0.49 mmol) and activation. The molecular sieve was heated to 125° C. for 18 hours. The reaction was cooled to room temperature and NaBH ₄ (40 mg, 1.06 mmol) was added followed by EtOH (4 ml). The reaction mixture was stirred for 1 hour. The reaction was quenched by the dropwise addition of 1M HCl (10 drops). Once effervescence ceased, water was added (10 ml), using a _2M K 2 CO _3, pH was adjusted to 10. The mixture was filtered and the aqueous layer was extracted with EtOAc (3 x 20 ml). The combined organic layers were dried (NaSO ₄ ), filtered and evaporated to give a brown oily solid (176 mg). Purification by flash column chromatography (eluting with a gradient of 0-10% MeOH/DCM) gave a brown solid (40 mg). Further purification by basic preparative HPLC gave a yellow oil (21 mg). Repurification by flash column chromatography (eluting with a gradient of 0-5% EtOH/DCM) gave the title compound (12 mg, 6%) as a pale yellow solid.

1H-NMR (Methanol-d4, 250MHz): d [ppm] = 8.38-8.32 (m, 1H), 7.90 (s, 1H), 7.65-7.55 (m, 3H). , 7.42-7.36 (m, 1H), 7.36-7.30 (m, 2H), 4.73 (d, J=1.6Hz, 2H), 3.60 (t, J=). 14.0 Hz, 2H), 3.20-3.08 (m, 4H)
HPLCMS (Method D): [m/z]: 461.2 [M+H] ^+.
General Scheme 11 above:
General Procedure 12: Ethyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-chloro-1,3-thiazole-4-carboxylate (184).

Ethyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate (1) (2 g, 6.66 mmol) and hexachloroethane (1.49 g, 6. A solution of 32 mmol) in THF (140 ml) was cooled to -78 °C. 2M NaHMDS (7.0 ml, 14.0 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 1 h, quenched with saturated NH ₄ Cl (aq) and allowed to warm to room temperature. The mixture was filtered and the residue was rinsed with THF (50 ml). The filtrate was evaporated in vacuo and the residue was partitioned between EtOAc and saturated _NH 4 Cl (aq). The organic layer was separated, dried (MgSO _4), and concentrated in vacuo. Purification by silica flash chromatography (eluting with a gradient of 0-30% EtOAc/DCM) gave the title compound (1.47 g, 65%) as a white solid.

_{1H-NMR (CDCl 3, 250MHz} ): d [ppm] = 4.91 (s, 1H), 4.45 (q, J = 7.1Hz, 2H), 3.55 (q, J = 6.3Hz , 2H), 3.18 (t, J=6.4 Hz, 2H), 1.49-1.39 (m, 12H).
HPLCMS (Method A): [m/z]: 356.95 [M+H] ^+.
2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-chloro-1,3-thiazole-4-carboxylic acid (185)

In a similar manner using general procedure 5 LiOH (739 mg, 30.84 mmol) and ethyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl) in THF (30 ml)/water (10 ml). -5-Chloro-1,3-thiazole-4-carboxylate (184) (1.47g, 4.41mmol) gave the title compound (1.35g, quantitative) as a yellow oil. The compound was used in the next step without further purification.

_{1H-NMR (CDCl 3, 500MHz} ): d [ppm] = 4.92 (s, 1H), 3.58 (q, J = 5.7Hz, 2H), 3.18 (t, J = 5.8Hz , 2H), 1.46 (s, 9H)
HPLC MS (Method A): [m/z]: 328.9 [M+H] ^+.
tert-Butyl N-[2-(5-chloro-4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (186)

In a similar manner using general procedure 6 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-chloro-1,3-thiazole-4-carboxylic acid in DCM (30 ml). (185) (800 mg, 2.61 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride-(A2) (623 mg, 3.13 mmol), DIPEA (1.5 ml, 10.0 mmol), HATU( After purification by flash column chromatography (eluting with a gradient of 0-60% EtOAc/heptane) by 1.19 g, 3.0 mmol), the title compound (1.08 g, 80%) was obtained as a white solid. The compound was used in the next step without further purification.

_{1H-NMR (CDCl 3, 250MHz} ): d [ppm] = 8.49-8.39 (m, 2H), 7.44 (ddd, J = 9.4,8.4,1.3Hz, 1H) , 7.34-7.23 (m, 3H), 4.94 (s, 1H), 4.84 (dd, J=5.1, 1.7 Hz, 2H), 3.59 (q, J=). 6.3 Hz, 2H), 3.15 (t, J=6.4 Hz, 2H), 1.46 (s, 9H)
HPLCMS (Method A): [m/z]: 415 [M+H] ^+.
tert-Butyl N-[2-(5-chloro-4-{[(3-chloropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (187)

In a similar manner using general procedure 6, 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-chloro-1,3-thiazole in tetrahydrofuran (10 ml)/DMF (2 ml). -4-carboxylic acid (185) (220 mg, 0.72 mmol), (3-chloropyridin-2-yl)methanamine dihydrochloride (154.55 mg, 0.72 mmol), DIPEA (0.26 ml, 2 mmol), HATU. After purification by flash column chromatography (eluting with a gradient of 20-60% EtOAc/heptane) by (0.33 g, 0.85 mmol), the title compound (360 mg, quantitative) was obtained as a white solid. The compound was used in the next step without further purification.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.66 (s, 1H), 8.56-8.52 (m, 1H), 7.74 (dd, J=8.0, 1). .4 Hz, 1H), 7.24 (dd, J=8.0, 4.7 Hz, 1H), 4.98 (s, 1H), 4.85 (d, J=4.8 Hz, 2H), 3 .61 (q, J=6.1 Hz, 2H), 3.17 (t, J=6.3 Hz, 2H), 1.46 (s, 9H).
HPLCMS (Method A): [m/z]: 431.1 [M+H]+.
tert-Butyl N-(2-{5-chloro-4-[(pyridin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate (188)

In a similar manner using general procedure 6 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-chloro-1,3-thiazole-4-carboxylic acid in tetrahydrofuran (10 ml). (185) (216 mg, 0.7 mmol), pyridin-2-ylmethanamine (0.09 ml, 0.84 mmol), DIPEA (0.26 ml, 1 mmol), HATU (0.32 g, 0.84 mmol) at room temperature. It was stirred. Further pyridin-2-ylmethanamine (0.09 ml, 0.84 mmol), DIPEA (0.26 ml, 0 mol) and HATU (0.32 g, 0 mol) were added and the reaction was continued. The title compound (227 mg, 78%) was isolated as a brown oil after purification by flash column chromatography (eluting with a gradient of 5-100% EtOAc/heptane). The compound was used in the next step without further purification.

1H-NMR (Methanol-d4, 250MHz): d [ppm] = 8.50 (d, J = 4.4Hz, 1H), 7.81 (td, J = 7.8, 1.5Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.36-7.27 (m, 1H), 4.73 (s, 3H), 4.68 (s, 2H), 3.13 ( t, J=6.4 Hz,
2H), 1.41 (s, 9H).
HPLC MS (Method A): [m/z]: 397.10 [M+H] ^+.
tert-Butyl N-(2-{5-chloro-4-[(pyridazin-3-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate (189)

2-(2-{[(tert-Butoxy)carbonyl]amino}ethyl)-5-chloro-1,3-thiazole-4-carboxylic acid in DCM (20 ml) in a similar manner using general procedure 6. Flash column chromatography by (185) (220 mg, 0.72 mmol), pyridazin-3-ylmethanamine (0.12 g, 1 mmol), DIPEA (0.31 ml, 2 mmol), HATU (0.41 g, 1 mmol). After purification by elution with a gradient of 50-100% EtOAc/heptane then 2-6% methanol/ethyl acetate) the title compound (278 mg, 91%) was obtained as a yellow residue. The compound was used in the next step without further purification.

HPLC MS (Method A): [m/z]: 398.05 [M+H] ^+.
tert-Butyl N-(2-{5-chloro-4-[(pyrimidin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate (190)

In a similar manner using general procedure 6, 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-chloro-1,3-thiazole in tetrahydrofuran (10 ml)/DMF (2 ml). -4-carboxylic acid (185) (579 mg, 1.54 mmol), 1-(pyrimidin-2-yl)methanamine (0.14 g, 1.28 mmol), DIPEA (0.67 ml, 3.85 mmol), HATU (0 0.585 g, 1.54 mmol) after purification by flash column chromatography (eluting with a gradient of 50-100% EtOAc/heptane) to give the title compound (0.483 g, 73%) as a white solid. The compound was used in the next step without further purification.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.83-8.79 (m, 1H), 8.78 (d, J=4.9 Hz, 2H), 7.41 (t, J=4.9 Hz, 1 H), 7.11-7.05 (m, 1 H), 4.64 (d, J=5.9 Hz, 2 H), 3.09 (t, J=6.6 Hz, 2 H ), 1.37 (s, 9H).
HPLC MS (Method A): [m/z]: 398 [M+H] ^+.
tert-Butyl N-[2-(5-chloro-4-{[(5-methylpyrimidin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (191)

In a similar manner using General Procedure 6 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-chloro-1,3-thiazole in tetrahydrofuran (10 ml)/DMF (2 ml). -4-carboxylic acid (185) (556 mg, 1.48 mmol) (5-methylpyrimidin-2-yl)methanamine (0.14 g, 1.14 mmol), DIPEA (0.396 ml, 2.274 mmol), HATU (0 0.562 g, 1.478 mmol) afforded the title compound (577 mg, 92%) as a colorless oil after purification by flash column chromatography (eluting with a gradient of 70-100% EtOAc/heptane). The compound was used in the next step without further purification.

1H-NMR (DMSO-d6,500 MHz) δ 8.77 (t, J=5.8 Hz, 1H), 8.63 (s, 2H), 7.08 (s, 1H), 4.60 (d, J=5.9 Hz, 2H), 3.09 (t, J=6.6 Hz, 2H), 2.27 (s, 3H), 1.37 (s, 9H).
HPLCMS (Method A): [m/z]: 412.05 [M+H] ^+.
2-(2-Aminoethyl)-5-chloro-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide (192)

In a similar manner using General Procedure 2 at room temperature 12M HCl (8 ml) in MeOH (40 ml) and tert-butyl N-[2-(5-chloro-4-{[(3-fluoropyridine-2- Yl) Methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (186) (1 g, 2.41 mmol) with an SCX-2 cartridge (gradient elution 100% DCM followed by 100% MeOH). After purification with 7N NH ₃ /MeOH, the title compound (703 mg, 93%) was obtained as a white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.73 (t, J=5.6 Hz, 1H), 8.40 (dt, J=4.6, 1.4 Hz, 1H), 7.71 (ddd, J=10.0, 8.3, 1.2 Hz, 1H), 7.42 (dt, J=8.6, 4.4 Hz, 1H), 4.63 (dd, J= 5.7, 1.5Hz, 2H), 3.02 (t, J = 6.0Hz, 2H), 2.93 (t, J = 6.1Hz, 2H)
HPLC MS (Method A): [m/z]: 314.95 [M+H] ^+.
2-(2-Aminoethyl)-5-chloro-N-[(3-chloropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide (193)

In a similar manner using general procedure 2 at room temperature 12M HCl in MeOH (10 ml) (2 ml) and tert-butyl N-[2-(5-chloro-4-{[(3-chloropyridine-2. -Yl)Methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (187) (360 mg, 0.83 mmol) afforded the title compound (320 mg, 95%) as a white solid.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.93 (t, J=6.0 Hz, 1H), 8.52 (dd, J=4.7, 1.3 Hz, 1H), 8.04 (s, 2H), 7.97 (dd, J=8.1, 1.4 Hz, 1H), 7.40 (dd, J=8.1, 4.7 Hz, 1H), 4.68 (D, J=5.8 Hz, 2H), 3.36-3.26 (m, 4H)
HPLCMS (Method A): [m/z]: 331.1 [M+H] ^+.
2-(2-Aminoethyl)-5-chloro-N-(pyridin-2-ylmethyl)-1,3-thiazole-4-carboxamide dihydrochloride (194)

In a similar manner using general procedure 2 at room temperature 12M HCl (2 ml) in MeOH (10 ml) and tert-butyl N-(2-{5-chloro-4-[(pyridin-2-ylmethyl)carbamoyl). ]-1,3-Thiazol-2-yl}ethyl)carbamate (188) (260 mg, 0.66 mmol) afforded the title compound (198 mg, 82%) as a dark yellow gum. The crude product was used without further purification.

1H-NMR (Methanol-d4, 250MHz): d [ppm] = 8.80 (d, J = 5.4Hz, 1H), 8.64 (td, J = 8.0, 1.3Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 8.03 (t, J=6.7 Hz, 1H), 4.99 (s, 2H), 3.60-3.39 (m, 4H) )
2-(2-Aminoethyl)-5-chloro-N-(pyridazin-3-ylmethyl)-1,3-thiazole-4-carboxamide dihydrochloride (195)

In a similar manner using General Procedure 2 at 60° C., 12M HCl (1.86 ml) in MeOH (10 ml) and tert-butyl N-(2-{5-chloro-4-[(pyridazine-3- Ilmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate (189) (278 mg, 0.65 mmol) provided the crude title compound (296 mg) as a pale brown residue. The crude product was taken to the next step without further purification.

HPLCMS (Method A): [m/z]: 298 [M+H] ^+.
2-(2-Aminoethyl)-5-chloro-N-(pyrimidin-2-ylmethyl)-1,3-thiazole-4-carboxamide dihydrochloride (196)

In a similar manner using General Procedure 2 at 40° C., 12M HCl (1.56 ml) in MeOH (3 ml) and tert-butyl N-(2-{5-chloro-4-[(pyrimidine-2- Ilmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate (190) (483 mg, 0.938 mmol) afforded the title compound (563 mg, 100%) as a beige solid.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.83(d, J=5.0Hz, 2H), 7.49(t, J=5.0Hz, 1H), 4.82( s, 2H), 3.49 (t, J=6.2 Hz, 2H), 3.39 (t, J=6.2 Hz, 2H)
HPLC MS (Method A): [m/z]: 297.9 [M+H] ^+.
2-(2-Aminoethyl)-5-chloro-N-[(5-methylpyrimidin-2-yl)methyl]-1,3-thiazole-4-carboxamide dihydrochloride (197)

In a similar manner using general procedure 2 at room temperature 12M HCl in MeOH (6 ml) (1.74 ml) and tert-butyl N-[2-(5-chloro-4-{[(5-methylpyrimidine 2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (191) (580 mg, 1.04 mmol) afforded the title compound (447 mg, 100%) as a white solid. .

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.74(s,2H),4.80(s,2H),3.49(t,J=6.2Hz,2H),3 .38 (t, J=6.2 Hz, 2H), 2.39 (s, 3H)
HPLCMS (Method A): [m/z]: 311.95 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-5-chloro-N-[(3-fluoropyridin-2-yl)methyl]-1,3- Thiazole-4-carboxamide (Example compound No. 151)

In a manner similar to general procedure 3, 2-(2-aminoethyl)-5-chloro-N-[(3-fluoropyridin-2-yl)methyl]-1 in MeOH (10 ml) at room temperature for 3 days. ,3-thiazole-4-carboxamide dihydrochloride (192) (143 mg, 0.37 mmol), 1H-1,3-benzodiazol-2-carbaldehyde (70.1 mg, 0.48 mmol), MgSO ₄ (200 mg). ), followed by NaBH ₄ (28 mg, 0.74 mmol) to give the title compound (94 mg, 56%) as a white solid after purification by preparative HPLC.

1H-NMR (DMSO-d6,500MHz): d[ppm]=12.19(s, 1H), 8.71(t, J=5.6Hz, 1H), 8.37(dt, J=4. 6,1.3 Hz, 1H), 7.70 (ddd, J=10.0, 8.4, 1.1 Hz, 1H), 7.54 (d, J=7.2 Hz, 1H), 7.45 (D, J=7.0 Hz, 1H), 7.40 (dt, J=8.6, 4.4 Hz, 1H), 7.14 (t, J=7.5 Hz, 2H), 4.66- 4.58 (m, 2H), 3.97 (s, 2H), 3.12 (t, J=6.3Hz, 2H), 2.94 (t, J=6.3Hz, 2H)
HPLCMS (Method A): [m/z]: 445.1 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-5-chloro-N-[(3-chloropyridin-2-yl)methyl]-1,3- Thiazole-4-carboxamide (Example compound 159)

2-(2-Aminoethyl)-5-chloro-N-[(3-chloropyridin-2-yl)methyl]-1 in MeOH (20 ml) for 16 hours at room temperature in a manner similar to general procedure 3. , 3-thiazole-4-carboxamide dihydrochloride (193) (320 mg, 0.79 mmol), 1H-1,3-benzodiazol-2-carbaldehyde (127.3 mg, 0.87 mmol), DIPEA (0. 32 ml, 2.0 mmol) and MgSO ₄ (300 mg), followed by NaBH ₄ (60 mg, 1.59 mmol) to give the title compound (191 mg, 52%) as a white solid after purification by preparative HPLC. Was given.

1H-NMR (DMSO-d6, 500MHz): d [ppm] = 12.18 (s, 1H), 8.72 (t, J = 5.6Hz, 1H), 8.49 (dd, J = 4. 7, 1.3 Hz, 1 H), 7.95 (dd, J=8.1, 1.3 Hz, 1 H), 7.54 (s, 1 H), 7.46 (s, 1 H), 7.38 ( dd, J=8.1, 4.7 Hz, 1H), 7.17-7.09 (m, 2H), 4.65 (d, J=5.5 Hz, 2H), 3.98 (d, J). =4.1 Hz, 2H), 3.13 (t, J=6.3 Hz, 2H), 2.95 (q, J=6.1, 5.3 Hz, 2H), 2.74 (s, 1H)
HPLCMS (Method C): [m/z]: 461 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-5-chloro-N-(pyridin-2-ylmethyl)-1,3-thiazole-4-carboxamide( Example compound No. 160)

In a similar manner to General Procedure 3, 2-(2-aminoethyl)-5-chloro-N-(pyridin-2-ylmethyl)-1, in DCM (10 ml) and MeOH (10 ml) at room temperature for 16 hours. 3-Thiazole-4-carboxamide dihydrochloride (194) (190 mg, 0.51 mmol), 1H-1,3-benzodiazol-2-carbaldehyde (113 mg, 0.77 mmol), DIPEA (0.3 ml, 2 0.0 mmol) and MgSO ₄ (400 mg) followed by NaBH ₄ (39 mg, 1.03 mmol) to give the title compound (60 mg, 27%) as a pale yellow solid after purification by preparative HPLC. ..

1H-NMR (DMSO-d6, 500MHz): d[ppm]=12.19(s, 1H), 8.90(t, J=6.0Hz, 1H), 8.50(d, J=5. 5 Hz, 1 H), 7.75 (td, J=7.7, 1.8 Hz, 1 H), 7.58-7.42 (m, 2 H), 7.31 (d, J=7.8 Hz, 1 H) ), 7.27 (dd, J=7.0, 5.3 Hz, 1H), 7.17-7.10 (m, 2H), 4.54 (d, J=6.0 Hz, 2H), 3 .98 (s, 2H), 3.12 (t, J=6.3Hz, 2H), 2.95 (t, J=6.3Hz, 2H), 2.76 (s, 1H)
HPLC MS (Method C): [m/z]: 427.1 [M+H] ^+.
5-Chloro -N- (pyridin-2-ylmethyl) -2- (2- {1,8,12- triazatricyclo [7.4.0.0 ^2, 7] trideca-2 (7), 3 ,5,8-Tetraen-12-yl}ethyl)-1,3-thiazole-4-carboxamide (Example compound 189)

In a similar manner to general procedure 8, 2-(2-aminoethyl)-5-chloro-N-(pyridin-2-ylmethyl)-1,3-thiazole-4 in MeCN (5 ml) at room temperature for 3 hours. -Carboxamide dihydrochloride (194) (361.5 mg, 0.98 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (187.9 mg, 0.98 mmol), DBU (219 μl, 1. 47 mmol) gave a mixture of monoalkylated and dialkylated intermediates which was separated by flash column chromatography (eluting with a gradient of 0-10% MeOH/EtOAc followed by 0-10% MeOH/DCM). did. Monoalkylated intermediate (5-chloro-2-[2-({2-[(2-nitrophenyl)carbamoyl]ethyl}amino)ethyl]-N-(pyridin-2-ylmethyl)-1,3-thiazole -4-carboxamide) (66.0 mg, 0.135 mmol) was further reacted with iron powder (15.1 mg, 0.270 mmol) in AcOH (1 ml) at 80° C. for 1 hour and flash column chromatography (0-10). After purification by elution with a gradient of% MeOH/DCM), the title compound (61 mg, 25%) was obtained as a brown oil.

¹ H NMR (Acetone-d6, 500 MHz): d[ppm]=8.53 (d, J=4.2 Hz, 2 H), 7.76 (td, J=7.7, 1.8 Hz, 1 H), 7.61-7.53 (m, 1H), 7.45-7.37 (m, 2H), 7.26 (dd, J=7.0, 4.9Hz, 1H), 7.22-7 .14 (m, 2H), 5.14 (s, 2H), 4.66 (d, J=5.7 Hz, 2H), 3.39 (t, J=6.2 Hz, 2H), 3.36. -3.28 (m, 2H), 3.20 (t, J=6.3Hz, 2H), 3.14 (t, J=6.2Hz, 2H)
HPLCMS (Method B): [m/z]: 453.1 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-5-chloro-N-(pyridazin-3-ylmethyl)-1,3-thiazole-4-carboxamide( Example compound No. 161)

In a manner similar to general procedure 3, 2-(2-aminoethyl)-5-chloro-N-(pyridazin-3-ylmethyl)-1, in DCM (10 ml) and MeOH (10 ml) at room temperature for 3 days. 3-thiazole-4-carboxamide dihydrochloride (195) (296 mg, 0.8 mmol), 1H-1,3-benzodiazol-2-carbaldehyde (151.7 mg, 1.04 mmol), DIPEA (0.42 ml). , 2.0 mmol) and MgSO ₄ (400 mg) followed by NaBH ₄ (60 mg, 1.59 mmol) to give the title compound (96 mg, 28%) as a white solid after purification by preparative HPLC. It was

1H-NMR (DMSO-d6, 500MHz): d [ppm] = 12.18 (s, 1H), 9.14 (dd, J = 4.8, 1.5Hz, 1H), 9.07 (t, J=6.1 Hz, 1H), 7.66 (dd, J=8.5, 4.8 Hz, 1H), 7.60 (dd, J=8.5, 1.6 Hz, 1H), 7.54 (D, J=7.4 Hz, 1H), 7.45 (d, J=7.7 Hz, 1H), 7.13 (p, J=7.0, 6.6 Hz, 2H), 4.72( d, J=6.1 Hz, 2H), 3.97 (s, 2H), 3.12 (t, J=6.3 Hz, 2H), 2.95 (t, J=6.2 Hz, 2H), 2.75 (s, 1H)
HPLCMS (Method C): [m/z]: 428 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-5-chloro-N-(pyrimidin-2-ylmethyl)-1,3-thiazole-4-carboxamide( (Example compound No. 175)

In a similar manner to General Procedure 3, 2-(2-aminoethyl)-5-chloro-N-(pyrimidin-2-ylmethyl)-1,3-thiazole-4 in MeOH (15 ml) at room temperature for 24 hours. - carboxamide dihydrochloride (196) (563mg, 0.94mmol) , 1H- benzimidazol-2-carbaldehyde (178mg, 1.22mmol), DIPEA ( 0.654ml, 0.74mmol), followed by NaBH ₄ (53 mg , 1.41 mmol) was added to give the title compound (224 mg, 54%) as a white solid after purification by preparative HPLC.

1H-NMR (DMSO-d6,500MHz): d[ppm]=12.20 (br s, 1H), 8.80-8.74 (m, 3H), 7.50 (br s, 2H), 7 .40 (t, J=4.9 Hz, 1H), 7.21-7.07 (m, 2H), 4.64 (d, J=5.9 Hz, 2H), 3.98 (s, 2H). , 3.13 (t, J=6.3 Hz, 2H), 2.96 (t, J=6.3 Hz, 2H), 2.76 (br s, 1H)
HPLC MS (Method G): [m/z]: 428.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-5-chloro-N-[(5-methylpyrimidin-2-yl)methyl]-1,3- Thiazole-4-carboxamide (Example compound No. 178)

In a similar manner to General Procedure 3, 2-(2-aminoethyl)-5-chloro-N-[(5-methylpyrimidin-2-yl)methyl]-1 in MeOH (6 ml) for 24 hours at room temperature. , 3-thiazole-4-carboxamide dihydrochloride (197) (223 mg, 0.52 mmol), 1H-benzimidazole-2-carbaldehyde (99 mg, 0.68 mmol), DIPEA (0.363 ml, 2.09 mmol) and After purification by preparative HPLC by addition of MgSO ₄ (400 mg) followed by NaBH ₄ (30 mg, 0.78 mmol) the title compound (120 mg, 52%) was obtained as a white solid.

1H-NMR (DMSO-d6,500MHz): d[ppm]=12.21(s, 1H), 8.72(t, J=5.8Hz, 1H), 8.63-8.57(m, 2H), 7.50 (s, 1H), 7.14 (dd, J=6.0, 2.7Hz, 2H), 4.61-4.56 (m, 2H), 3.98 (s, 2H), 3.13 (t, J=6.3 Hz, 2H), 2.95 (t, J=6.3 Hz, 2H), 2.75 (s, 1H), 2.26 (s, 3H).
HPLCMS (Method C): [m/z]: 442 [M+H] ^+.
5-chloro-N-[(3-fluoropyridin-2-yl)methyl]-2-[2-({2-[(2-nitrophenyl)carbamoyl]ethyl}amino)ethyl]-1,3-thiazole -4-carboxamide (198)

2-(2-Aminoethyl)-5-chloro-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide (192 ) (700 mg, 2.22 mmol) and N-(2-nitrophenyl)prop-2-enamide (D) (470 mg, 2.45 mmol) in MeCN (40 ml) and DBU (0.37 ml, 2.0 mmol). ) Was added. The mixture was stirred at room temperature for 3 days. The reaction mixture was evaporated directly on silica. Purification by flash column chromatography (eluting with a gradient of 0-10% MeOH/DCM) gave the title compound (390 mg, 25%) as a yellow solid.

HPLCMS (Method A): [m/z]: 507 [M+H] ^+.
2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-5-chloro-N-[(3-fluoropyridin-2-yl)methyl] -1,3-thiazole-4-carboxamide trihydrochloride (Example compound No. 154)

In a similar manner to General Procedure 8 for 5 min at 90° C. in AcOH (5 ml) 5-chloro-N-[(3-fluoropyridin-2-yl)methyl]-2-[2-({2- [(2-Nitrophenyl)carbamoyl]ethyl}amino)ethyl]-1,3-thiazole-4-carboxamide (198) (390 mg, 0.77 mmol) and iron powder (172 mg, 3 mmol) gave the crude product. It was The residue was purified by silica plug, flowing through gradient elution 0.5 to 40% MeOH / DCM, then MeOH / DCM in 20% 7M NH _3, and purified by preparative HPLC further basic prep subsequently, the necessary product free base Got as. The residue was redissolved in MeOH (10 ml) and treated with 12M HCl (1 ml) for 1 hour. Strict removal of the solvent under vacuum gave the target compound as a pale yellow solid.

1H-NMR (D ₂ O, 500 MHz): d[ppm]=8.33-8.30 (m, 1H), 7.87 (ddd, J=9.6, 8.6, 1.2 Hz, 1H). ), 7.71 (dt, J=6.8, 3.4 Hz, 2H), 7.59 (dt, J=7.5, 4.2 Hz, 1H), 7.55 (dt, J=6. 3,3.4 Hz, 2H), 3.72-3.62 (m, 6H), 3.44 (t, J=6.6Hz, 2H). Benzylic CH ₂ signals, it should be noted that the hidden by D2 O.

HPLC MS (Method A): [m/z]: 459.1 [M+H] ^+.
2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-5-chloro-N-[(5-methylpyrimidin-2-yl)methyl] -1,3-thiazole-4-carboxamide (Example compound No. 182)

In a similar manner using general procedure 8, 2-(2-aminoethyl)-5-chloro-N-[(5-methylpyrimidin-2-yl)methyl]-1,3- in MeCN (10 ml). Thiazole-4-carboxamide dihydrochloride (197) (0.223 g, 0.522 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (0.090 g, 0.47 mmol) and DBU(0. .171 ml, 1.148 mmol) gave the intermediate (355 mg, 0.46 mmol) which was further reacted with iron powder (104 mg, 1.86 mmol) in AcOH (5 ml) at 80° C. for 2.5 hours. After purification by basic preparative HPLC followed by flash column chromatography (eluting with a gradient of 0-5% MeOH/DCM), the title compound (6 mg, 3%) was obtained as an off-white solid.

1H-NMR (DMSO-d4,500MHz): d[ppm]=8.54 (s, 2H), 7.47-7.41 (m, 2H), 7.20-7.14 (m, 2H). , 4.62 (s, 2H), 3.23-3.16 (m, 4H), 3.15-3.10 (m, 4H), 2.28 (s, 3H).
HPLCMS (Method D): [m/z]: 456.2 [M+H] ^+.
2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-5-chloro-N-(pyridazin-3-ylmethyl)-1,3-thiazole -4-carboxamide (Example compound No. 183)

In a similar manner using general procedure 8, 2-(2-aminoethyl)-5-chloro-N-(pyridazin-3-ylmethyl)-1,3-thiazol-4-carboxamide bisdiamine in MeCN (5 ml). Intermediate with hydrochloride salt (195) (255 mg, 0.689 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (132 mg, 0.689) and DBU (0.154 ml, 1.03 mmol). (112 mg, 0.16 mmol) was obtained, which was further reacted with iron powder (18 mg, 0.33 mmol) in AcOH (1 ml) at 80° C. for 2.5 hours, and flash column chromatography (0-20% MeOH). / Gradient elution with DCM) followed by purification by basic preparative HPLC to give the title compound (6.4 mg, 8.5%) as a yellow oil.

1H-NMR (Methanol-d4,500MHz): d [ppm] = 9.08 (dd, J = 4.3, 2.3Hz, 1H), 7.72-7.63 (m, 2H), 7. 47 (dd, J=5.9, 3.2 Hz, 2H), 7.23-7.15 (m, 2H), 4.80 (s, 2H), 3.16-3.02 (m, 8H). )
HPLCMS (Method B): [m/z]:440.4 [MH] ^-
2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-5-chloro-N-(pyridin-2-ylmethyl)-1,3-thiazole -4-carboxamide (Example compound No. 184)

In a similar manner using General Procedure 8, 2-(2-Aminoethyl)-5-chloro-N-(pyridin-2-ylmethyl)-1,3-thiazole-4-carboxamidediamine in MeCN (5 ml). Hydrochloride (194) (361.6 mg, 0.978 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (187.9 mg, 0.978 mmol), DBU (0.219 ml, 1.467 mmol). ) Gave the intermediate (180 mg, 0.26 mmol) which was further reacted with iron powder (29 mg, 0.54 mmol) in AcOH (1 ml) at 80° C. for 2 hours after purification by basic preparative HPLC. , The title compound (8.8 mg, 7.5%) was obtained as a yellow oil.

1H-NMR (Methanol-d4,500MHz): d [ppm] = 8.47 (ddd, J = 5.0, 1.6, 0.9Hz, 1H), 7.77 (td, J = 7.7). , 1.8 Hz, 1H), 7.47 (dd, J=5.9, 3.2 Hz, 2H), 7.37 (d, J=7.9 Hz, 1H), 7.33-7.25( m, 1H), 7.20-7.16 (m, 2H), 4.61 (s, 2H), 3.16-3.01 (m, 8H)
HPLCMS (Method B): [m/z]: 439.3 [MH] ^-
Ethyl 5-bromo-2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate (199)

Ethyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate (1) (1.56 g, 5.19 mmol) and 1,2-dibromo-1. , 1,2,2-Tetrachloroethane (1.86 g, 10.0 mmol) was dissolved in THF (60 ml) and cooled to -78°C. 2M NaHMDS (5.45 ml) was added dropwise and the mixture was stirred at -78°C for 2 hours. The reaction was quenched with saturated NH ₄ Cl (aq) (30 ml) and allowed to warm to room temperature. The mixture was extracted with DCM (3 × 100ml), dried the combined organic extracts _(Na 2 _SO 4), filtered and evaporated in vacuo. Purification by flash column chromatography with gradient elution 10-50% EtOAc/heptane gave the title compound (1.62 g, 80%) as a colorless oil.

_{1H-NMR (CDCl 3, 250MHz} ): d [ppm] = 4.91 (s, 1H), 4.46 (q, J = 7.1Hz, 2H), 3.56 (q, J = 6.3Hz , 2H), 3.21 (t, J=6.3 Hz, 2H), 1.50-1.42 (m, 12H).
HPLC MS (Method A): [m/z]: 400.9/402.85 [M+H] ^+.
2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-(prop-1-en-2-yl)-1,3-thiazol-4-carboxylate (200)

Ethyl 5-bromo-2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate (199) (626 mg, 1.65 mmol), PdCl ₂ (dppf). (120 mg, 0.17 mmol) and _{K 2 CO 3 (460mg, 3.0mmol} ) was dissolved in MeCN (18 ml) and water (18 ml) under nitrogen, 4,4,5,5-tetramethyl-2- ( Propa-1-en-2-yl)-1,3,2-dioxaborolane (0.38 ml, 1.98 mmol) was added. The mixture was heated at 80° C. for 30 minutes, cooled to room temperature and diluted with water. The mixture was extracted with DCM (3 × 80ml), dried the combined organic extracts _(Na 2 _SO 4), filtered and evaporated in vacuo. Purification by flash chromatography with gradient elution 10-60% EtOAc/heptane gave the title compound (558 mg, 99%) as a yellow oil.

1H-NMR (CDCl ₃ , 250 MHz): d[ppm]=5.23 (s, 1H), 5.12 (s, 1H), 4.94 (s, 1H), 4.32 (q, J= 7.2Hz, 2H), 3.47(q, J=6.5Hz, 2H), 3.09(t, J=6.5Hz, 2H), 2.07(s, 3H), 1.37( s, 9H), 1.31 (t, J=7.2Hz, 3H).
HPLCMS (Method A): [m/z]: 341.05 [M+H] ^+.
Ethyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-(trifluoromethyl)-1,3-thiazole-4-carboxylate (201)

Ethyl 5-bromo-2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate (199) (0.54 g, 1.43 mmol) under nitrogen. Dissolved in DMF (30 ml), copper(I) iodide (1.36 g, 7.0 mmol), triphenylarsane (0.14 ml, 0.57 mmol), Pd ₂ dba ₃ (0.065 g, 0.07 mmol) and methyldifluoro(fluorosulfonyl)acetate (0.23 ml, 1.85 mmol) were added. The mixture was heated at 100° C. for 3 hours, then cooled to room temperature and concentrated in vacuo. The residue was partitioned between saturated NaHCO ₃ (aq) and EtOAc. The phases were separated, the aqueous phase extracted with EtOAc (2 x 80 ml), the combined organic extracts washed with brine (2 x 50 ml), dried (Na ₂ SO ₄ ), filtered and in vacuo. Evaporated. Purification by flash column chromatography (eluting with a gradient of 10-60% EtOAc/heptane) gave the title compound (0.447g, 84%) as a yellow oil.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=4.92 (s, 1H), 4.48 (q, J=7.1 Hz, 2H), 3.60 (q, J=6. 2Hz, 2H), 3.27(t, J=6.2Hz, 2H), 1.46(s, 9H), 1.44(t, J=7.1Hz, 3H)
HPLCMS (Method A): [m/z]: 391 [M+Na] ^+.
2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-(prop-1-en-2-yl)-1,3-thiazole-4-carboxylic acid (202)

In a manner similar to General Procedure 5, ethyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-(prop-1-ene-2 in THF (20 ml) and water (20 ml). -Yl)-1,3-thiazol-4-carboxylate (200) (550 mg, 1.62 mmol) and LiOH (390 mg, 16.0 mmol) gave the crude title compound (569 mg, quantitative) as a yellow oil. It was

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=5.41 (s, 1H), 5.38 (s, 1H), 4.84 (s, 1H), 3.59 (m, 2H). , 3.16 (t, J=6.4 Hz, 2H), 2.23 (s, 3H), 1.47 (s, 9H)
HPLC MS (Method A): [m/z]: 312.9 [M+H] ^+.
2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-(trifluoromethyl)-1,3-thiazole-4-carboxylic acid (203)

In a manner similar to General Procedure 5, ethyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-(trifluoromethyl)-1, in THF (15 ml) and water (15 ml). 3-Thiazole-4-carboxylate (201) (447 mg, 1.21 mmol) and LiOH (320 mg, 13.0 mmol) gave the title compound (365 mg, 88%) as a pale yellow solid.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=4.81 (s, 1H), 3.53 (q, J=6.0 Hz, 2H), 3.18 (br s, 2H), 1 .37 (s, 9H)
HPLC MS (Method A): [m/z]: 362.95 [M+Na] ^+.
tert-Butyl N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-5-(prop-1-en-2-yl)-1,3-thiazole-2- (Il) ethyl] carbamate (204)

In a similar manner to general procedure 6, 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-(prop-1-en-2-yl)-1, in DCM (20 ml). 3-Thiazol-4-carboxylic acid (202) (569 mg, 1.82 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (435 mg, 2.19 mmol), DIPEA (1.11 ml, 6.0 mmol), HATU (830 mg, 2.0 mmol) after purification by flash column chromatography (eluting with a gradient of 0-60% EtOAc/heptane) to give the title compound (544 mg, 71%) as a colorless oil. It was

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.51-8.43 (m, 2H), 7.45-7.38 (m, 1H), 7.30-7.24 (m , 1H), 5.34 (m, 1H), 5.27 (s, 1H), 4.83 (dd, J=5.1, 1.6Hz, 2H), 3.61 (m, 2H), 3.15 (m, 2H), 2.25 (s, 3H), 1.46 (s, 9H).
HPLCMS (Method A): [m/z]: 421.05 [M+H] ^+.
tert-butyl N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-5-(trifluoromethyl)-1,3-thiazol-2-yl)ethyl]carbamate( 205)

In a similar manner to general procedure 6 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-(trifluoromethyl)-1,3-thiazole-4- in DCM (20 ml). Carboxylic acid (203) (365 mg, 1.07 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (256.2 mg, 1.29 mmol), DIPEA (0.65 ml, 4 mmol) and HATU. (490 mg, 1.3 mmol) afforded the title compound (344 mg, 72%) after purification by flash column chromatography (eluting with a gradient of 20-30% EtOAc/heptane).

1H-NMR (CDCl ₃ , 250 MHz): d[ppm]=8.49 (s, 1H), 8.35 (dt, J=4.6, 1.3 Hz, 1H), 7.35 (ddd, J). =9.4, 8.4, 1.3 Hz, 1H), 7.25-7.15 (m, 1H), 4.85 (s, 1H), 4.77 (dd, J=5.0, 1.6Hz, 2H), 3.54(q, J=6.3Hz, 2H), 3.17(t, J=6.3Hz, 2H), 1.37(s, 9H)
HPLC MS (Method A): [m/z]: 449.05 [M+H] ^+.
2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-(prop-1-en-2-yl)-1,3-thiazol-4-carboxamide dihydrochloride Salt (206)

In a manner similar to General Procedure 2, tert-butyl N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-5-(prop-1-- in MeOH (10 ml). En-2-yl)-1,3-thiazol-2-yl)ethyl]carbamate (204) (544 mg, 1.29 mmol) and 12M HCl (2 ml) gave the title compound (486 mg, 94%) as a white solid. Was obtained.

HPLCMS (Method A): [m/z]: 321 [M+H] ^+.
2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-(trifluoromethyl)-1,3-thiazole-4-carboxamide dihydrochloride (207)

In a manner similar to General Procedure 2 tert-butyl N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-5-(trifluoromethyl) in MeOH (10 ml). -1,3-Thiazol-2-yl)ethyl]carbamate (205) (347 mg, 0.77 mmol) and 12M HCl (2 ml) gave the title compound (330 mg, quantitative) as a white solid.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=9.22 (t, J=5.6 Hz, 1H), 8.40 (dt, J=4.6, 1.4 Hz, 1H), 8.16 (s, 3H), 7.74 (ddd, J = 10.1, 8.4, 1.4Hz, 1H), 7.43 (dt, J = 8.4, 4.4Hz, 1H) , 4.68 (dd, J=5.8,
1.5Hz, 2H), 3.42-3.22 (m, 4H)
HPLCMS (Method A): [m/z]: 349 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-5-(prop-1-ene -2-yl)-1,3-thiazol-4-carboxamide (Example compound 177)

In a similar manner using general procedure 3 for 18 hours at room temperature 2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-( in MeOH (20 ml). Propa-1-en-2-yl)-1,3-thiazol-4-carboxamide dihydrochloride (206) (260 mg, 0.66 mmol), 1H-benzimidazole-2-carbaldehyde (96.6 mg, 0. 66 mmol), DIPEA (0.36 ml, 2.0 mmol) and MgSO ₄ (300 mg), followed by NaBH ₄ (500 mg, 1.3 mmol) to give the title compound (148 mg) after purification by basic preparative HPLC. , 50%) was obtained as a pale yellow solid.

1H-NMR (DMSO-d6,500MHz): d[ppm]=12.19(s, 1H), 8.67(t, J=5.5Hz, 1H), 8.36(d, J=4. 6 Hz, 1 H), 7.69 (t, J=8.8 Hz, 1 H), 7.58-7.43 (m, 2 H), 7.40 (m, 1 H), 7.16-7.09 ( m, 2H), 5.21 (s, 1H), 5.15 (s, 1H), 4.61 (d, J=5.5Hz, 2H), 3.97 (s, 2H), 3.11. (T, J=6.7 Hz, 2H), 2.96 (t, J=6.7 Hz, 2H), 2.08 (s, 3H)
HPLCMS (Method C): [m/z]: 451.1 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-5-(trifluoromethyl)- 1,3-thiazole-4-carboxamide (Example compound No. 176)

In a similar manner using general procedure 3 at room temperature for 16 hours 2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-( in MeOH (10 ml). Trifluoromethyl)-1,3-thiazole-4-carboxamide dihydrochloride (207) (130 mg, 0.31 mmol), 1H-benzimidazole-2-carbaldehyde (67.6 mg, 0.46 mmol), DIPEA (0 0.16 ml, 0.93 mmol) and MgSO ₄ (300 mg) followed by NaBH ₄ (23 mg, 0.62 mmol) to give the title compound (81 mg, 55%) as a pale product after purification by basic preparative HPLC. Obtained as a yellow solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.21 (s, 1H), 8.96 (t, J=5.7 Hz, 1H), 8.37 (dt, J=4. 6,1.3 Hz, 1H), 7.71 (ddd, J=10.0, 8.3, 1.3 Hz, 1H), 7.53 (s, 1H), 7.45 (s, 1H), 7.41 (dt, J=8.3, 4.4 Hz, 1H), 7.14 (s, 2H), 4.65 (dd, J=5.7, 1.4 Hz, 2H), 3.99 (S, 2H), 3.22 (t, J=6.3 Hz, 2H), 2.99 (t, J=6.3 Hz, 2H), 2.80 (s, 1H)
HPLC MS (Method C): [m/z]: 479.1 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-5-(propan-2-yl )-1,3-Thiazole-4-carboxamide (Example compound No. 180)

2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-5-(prop-1-ene 2-yl)-1,3-thiazol-4-carboxamide (Example Compound #177) (120 mg, 0.27 mmol) and palladium on carbon (10%, 28 mg, 0.027 mmol) in EtOH (10 ml). The mixture was stirred under hydrogen atmosphere for 1.5 hours. The reaction mixture was filtered through a Celite plug and the residue was rinsed with MeOH. The combined filtrate was evaporated in vacuo and purified by basic preparative HPLC to give the title compound (68 mg, 56%) as a white solid.

1H-NMR (DMSO-d6,500MHz): d[ppm]=12.20(s, 1H), 8.60(t, J=5.6Hz, 1H), 8.38-8.34(m, 1H), 7.70 (m, 1H), 7.58-7.43 (m, 2H), 7.40 (dt, J=8.6, 4.4Hz, 1H), 7.16-7. 09 (m, 2H), 4.63 (dd, J=5.6, 1.4 Hz, 2H), 4.24 (hept, J=6.8 Hz, 1H), 3.96 (s, 2H), 3.11 (t, J=6.8Hz, 2H), 2.95 (t, J=6.8Hz, 2H), 1.21 (d, J=6.8Hz, 6H)
HPLC MS (Method C): [m/z]: 453.2 [M+H] ^+.
2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-( Trifluoromethyl)-1,3-thiazole-4-carboxamide (Example compound No. 186)

In a similar manner using general procedure 8 2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-(trifluoromethyl)- in MeCN (10 ml). 1,3-thiazole-4-carboxamide dihydrochloride (207) (242 mg, 0.57 mmol), N-(2-nitrophenyl)prop-2-enamide (110.4 mg, 0.57 mmol) and DBU (0. 301 ml, 2 mmol) to give the crude intermediate which was further reacted with iron powder (56 mg, 1 mmol) in AcOH (3 ml) and purified twice by basic preparative HPLC and flash column chromatography (0 to 0). After final purification by elution with a gradient of 20% MeOH/DCM), the title compound (4 mg, 2%) was obtained.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.14 (s, 1H), 8.94 (t, J=5.5 Hz, 1H), 8.39 (dt, J=4. 5,1.4 Hz, 1H), 7.71 (ddd, J=9.9, 8.3, 1.4 Hz, 1H), 7.41 (m, 2H), 7.10 (m, 2H), 4.64 (dd, J=5.7, 1.4 Hz, 2H), 3.18 (t, J=6.1 Hz, 2H), 3.06 (t, J=6.1 Hz, 2H), 3 .02-2.92 (m, 4H)
HPLCMS (Method C): [m/z]: 493.1 [M+H] ^+.
2-(Ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid (216)

3-Bromo-2-oxopropanoic acid and ethylamino(thioxo)acetate in THF (100 ml) were stirred at 60° C. for 16 hours. The reaction mixture was concentrated in vacuo to give an orange solid. The solid was triturated with Et ₂ O, filtered and dried in vacuo to give the title compound (4.54g, 62.8%) as a colorless solid.

1H-NMR (DMSO-d6,500MHz): d[ppm]=13.40(s,1H),8.77(s,1H),4.40(q,J=7.1Hz,2H),1 .35 (t, J=7.1Hz, 3H)
HPLC MS (ESI+): [m/z]: 201.90 [M+H] ^+.
Ethyl 4-(hydroxymethyl)-1,3-thiazole-2-carboxylate (217)

Isobutyl chloroformate (1.16 ml, 8.95 mmol) was added to 2-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid (216) (1.5 g, 7.46 mmol) and TEA (1.25 ml). , 8.95 mmol) in THF (60 ml) in ice-cold (0° C.) suspension. The reaction was stirred at 0° C. for 1 hour. The reaction was filtered through a Celite plug, NaBH ₄ (0.705 g, 18.64 mmol) was added to the filtrate and stirred for 2 hours. The reaction was diluted with saturated aqueous Na ₂ CO ₃ solution, stirred for 10 min, then extracted with EtOAc. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and the solvent was evaporated. Purification by flash column chromatography (eluting with a gradient of 40-50% EtOAc-Heptane) provided the title compound (0.734g, 52.6%) as a crystalline solid.

1H-NMR (DMSO-d6,500 MHz) d[ppm]=7.85 (s, 1H), 5.50 (t, J=5.8 Hz, 1H), 4.63 (dd, J=5.8). , 0.8 Hz, 2H), 4.37 (q, J=7.1 Hz, 2H), 1.33 (d, J=7.1 Hz, 3H)
HPLC MS (ESI+): [m/z]: 187.90 [M+H] ^+.
Ethyl 4-{[(benzyloxy)methoxy]methyl}-1,3-thiazole-2-carboxylate (218)

NaH (60%, 0.106 g, 2.66 mmol) was added to ethyl 4-(hydroxymethyl)-1,3-thiazole-2-carboxylate (217) (0.415 g, 2.22 mmol) in THF (20 ml). Add to medium ice cold (0° C.) solution and stir the reaction at 0° C. for 30 minutes. [(Chloromethoxy)methyl]benzene (0.416 g, 2.66 mmol) was added and the reaction was allowed to warm to room temperature over 3 hours. The reaction was quenched by the addition of saturated aqueous _NH 4 Cl and extracted with EtOAc. The combined organic layers were combined, washed with brine, dried (Na 2 _{SO 4),} filtered and the solvent was evaporated. Purification by flash column chromatography (eluting with 30-50% EtOAc-heptane) gave the title compound (0.392 g, 48.9%) as a colorless oil.

1H-NMR (CDCl ₃ , 500 MHz) d[ppm]=7.52-7.50 (m, 1H), 7.36-7.33 (m, 5H), 4.90 (s, 2H), 4 .86 (d, J=0.8 Hz, 2H), 4.66 (s, 2H), 4.48 (q, J=7.1 Hz, 2H), 1.44 (t, J=7.1, 3H).
HPLC MS (ESI+): [m/z]: 307.95 [M+H] ^+.
4-{[(benzyloxy)methoxy]methyl}-1,3-thiazole-2-carboxylic acid (219)

In a manner similar to General Procedure 5, LiOH (64 mg, 1.53 mmol) was treated with ethyl 4-{[(benzyloxy)methoxy]methyl}-1,3-thiazole-2-carboxylate (218) (85%). , 0.39 g, 1.28 mmol) in THF (5 ml), MeOH (5 ml) and water (5 ml) at room temperature for 4 hours to give the title compound (0.35 g, 88.4%) as a colorless oil. Was obtained.

1H-NMR (DMSO-d6,500 MHz) d[ppm]=7.95 (s, 1H), 7.36-7.33 (m, 5H), 4.84 (s, 2H), 4.74 ( s, 2H), 4.60 (s, 2H), 4.49 (s, 1H).
HPLC MS (ESI+): [m/z]: 279.95 [M+H] ^+.
4-{[(benzyloxy)methoxy]methyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-2-carboxamide (220)

In a similar manner to General Procedure 6, 4-{[(benzyloxy)methoxy]methyl}-1,3-thiazole-2-carboxylic acid (219) (0.350 g in DMF (10 ml) for 16 hours at room temperature. , 1.25 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (0.374 g, 1.88 mmol), DIPEA (0.89 ml, 5.01 mmol) and HATU (0.714 g, After purification by flash column chromatography (eluting with a gradient of 0-5% MeOH-DCM) by 1.88 mmol), the title compound (0.381 g, 76.1%) was obtained as a yellow oil.

1H-NMR (CDCl ₃ , 250 MHz) d[ppm]=8.42-8.38 (m, 1H), 7.40-7.27 (m, 7H), 4.90 (s, 2H), 4 .86-4.82 (m, 2H), 4.80 (d, J=0.6Hz, 2H), 4.68 (s, 2H)
HPLC MS (ESI+): [m/z]: 388.05 [M+H] ^+.
N-[(3-fluoropyridin-2-yl)methyl]-4-(hydroxymethyl)-1,3-thiazole-2-carboxamide (221)

TFA (1 ml, 13.06 mmol) was added to 4-{[(benzyloxy)methoxy]methyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-2-carboxamide (220). ) (0.185 g, 0.48 mmol) in DCM (4 ml) in ice-cold (0° C.) solution. The reaction was warmed to room temperature and stirred for 16 hours. The solvent was evaporated, the resulting residue was dissolved in EtOAc (5 ml), washed with saturated aqueous NaHCO ₃ solution (20 ml), brine (10 ml), dried (Na ₂ SO ₄ ), filtered and the solvent was evaporated. Let Purification by flash column chromatography (eluting with a gradient of 5% MeOH to DCM) provided the title compound (0.085g, 73.2%) as a colorless powder.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.45-8.41 (m, 1H), 8.36 (br s, 1H), 7.45 (s, 1H), 7.44. -7.40 (m, 1H), 7.31-7.26 (m, 1H), 4.85 (dd, J=5.1, 1.6Hz, 2H), 4.83 (d, J=) 5.6Hz, 2H), 2.20 (t, J=6.0Hz, 1H)
HPLC MS (ESI+): [m/z]: 267.95 [M+H] ^+.
N-[(3-fluoropyridin-2-yl)methyl]-4-formyl-1,3-thiazol-2-carboxamide (222)

IBX (189 mg, 0.70 mmol) was added to N-[(3-fluoropyridin-2-yl)methyl]-4-(hydroxymethyl)-1,3-thiazole-2-carboxamide (221) (60 mg, 0. 22 mmol) in MeCN (5 ml) was added and the reaction heated at 80° C. for 3 hours. The reaction was cooled to room temperature and filtered through Celite. The solution was absorbed directly onto silica and purified by flash column chromatography (eluting with a gradient of 5% MeOH-DCM). The product was re-purified by flash column chromatography (eluting with a gradient of 30-50% EtOAc-heptane) to give the title compound (56 mg, 94%) as a colorless solid.

_{1H-NMR (CDCl 3, 500MHz} ): d [ppm] = 10.10 (s, 1H), 8.46 (br s, 1H), 8.46-8.44 (m, 1H), 8.37 (S, 1H), 7.46-7.42 (m, 1H), 7.33-7.28 (m, 1H), 4.88 (dd, J=5.1, 1.7Hz, 2H).
HPLC MS (ESI+): [m/z]: 265.95 [M+H] ^+.
4-({[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}methyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole -2-carboxamide (Example compound No. 205)

A solution of N-[(3-fluoropyridin-2-yl)methyl]-4-formyl-1,3-thiazole-2-carboxamide (222) (56 mg, 0.21 mmol) in DCE (1 mL) was added to 2- (1H-1,3-benzodiazol-2-yl)ethan-1-amine dihydrochloride (50 mg, 0.21 mmol) and DIPEA (147 μl, 0.84 mmol) added to a suspension in DCE (2 ml). did. 4ÅActivated molecular sieves were added, the solution was stirred at room temperature for 2 hours, then filtered and the filtrate concentrated in vacuo. The residue was dissolved in MeOH (10 ml) and cooled to 0°C. NaBH ₄ (12 mg, 0.32 mmol) was added, the mixture was warmed to room temperature, stirred for 1 h, then quenched with saturated Na ₂ CO ₃ (aq) and extracted with EtOAc (2×10 ml). Dry the organic extracts combined _(Na 2 _SO 4), filtered and evaporated in vacuo. Purification by basic preparative HPLC gave the title compound (44 mg, 51%) as a colorless foam.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.31 (dt, J=4.5, 1.2Hz, 1H), 7.62(s, 1H), 7.57(ddd, J=9.8, 8.5, 1.2 Hz, 1H), 7.46 (dt, J=6.6, 3.3 Hz, 2H), 7.36 (dt, J=8.5, 4. 5 Hz, 1 H), 7.18-7.14 (m, 2 H), 4.75 (d, J=1.6 Hz, 2 H), 3.96 (s, 2 H), 3.13-3.07 ( m, 4H).
HPLCMS (Method C): [m/z]: 411.1 [M+H] ^+.
General Scheme 12 above
General Procedure 13: Methyl 2-(3-{[(tert-butoxy)carbonyl]amino}propanamide)-3-hydroxypropanoate (223).

TEA (8.38 ml, 60.1 mmol) was added to a cooled (0° C.) solution of methyl serate hydrochloride (1:1) (8.5 g, 54.6 mmol) in DCM (250 ml) under nitrogen. N-(tert-Butoxycarbonyl)-β-alanine (10.3 g, 54.6 mmol) and DCC (12.4 g, 60.1 mmol) were added in small portions. The reaction mixture was warmed to room temperature and stirred for 19 hours. The solvent was evaporated and EtOAc (250 ml) was added. The mixture was heated to 50° C., stirred for 20 minutes, cooled to room temperature and filtered. The filtrate was evaporated to give a waxy off-white solid (21.7g). The solid was dissolved in MeOH (200 ml) and silica (300 ml volume) was added. The solvent was evaporated under reduced pressure to give the compound dry-loaded on silica. Purification by flash column chromatography (20% EtOAc/heptane (2 L), 40% EtOAc/heptane (4 L), 80% EtOAc/heptane (2 L), followed by elution with a gradient of EtOAc (8 L) followed by the title compound ( 10.4 g, 64.4%) was obtained as an off-white solid.

_{1H-NMR (CDCl 3, 250MHz} ): d [ppm] = 6.62 (s, 1H), 5.12 (s, 1H), 4.65 (dt, J = 7.1,3.4Hz, 1H ), 3.96 (t, J=3.2 Hz, 2H), 3.80 (s, 3H), 3.55-3.33 (m, 2H), 2.95 (s, 1H), 2. 48 (td, J=5.8, 2.6 Hz, 2H), 1.43 (s, 9H)
HPLCMS (Method A): [m/z]: 291 [M+H] ^+.
Methyl 2-(2-{[(tert-butoxy)carbonyl]amino}acetamido)-3-hydroxypropanoate (224)

In a manner similar to general procedure 13, serine methyl ester hydrochloride (3 g, 19.28 mmol) in DCM (100 ml), TEA (2.96 ml, 21.21 mmol), N-(tert-butoxycarbonyl)glycine (3 .38 g, 19.28 mmol) and DCC (4.38 g, 21.21 mmol) after purification by flash chromatography using an elution gradient 20-100% EtOAc/heptane to give the title compound (4.5 g, 69%) as a pale product. Obtained as a yellow oil.

1H-NMR (CDCl ₃ , 250 MHz): d[ppm]=7.07 (d, J=7.4 Hz, 1H), 5.32 (s, 1H), 4.77-4.60 (m, 1H). ), 3.99 (m, 2H), 3.87 (m, 2H), 3.81 (s, 3H), 3.04 (s, 1H), 1.48 (s, 9H).
HPLC MS (Method A): [m/z]: 298.95 [M+Na] ^+.
General Procedure 14: Methyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-4,5-dihydro-1,3-oxazole-4-carboxylate (225).

Methyl 2-(3-{[(tert-butoxy)carbonyl]amino}propanamide)-3-hydroxypropanoate (223) (98%, 10.42 g, 35.17 mmol) under nitrogen was added to anhydrous DCM (280 ml). ) Dissolved in. The reaction mixture was cooled in _CO 2 / MeCN bath (about -50 ° C.), and stirred for 30 minutes. DAST (5.58 ml, 42.21 mmol) was added dropwise and the mixture was stirred at -50°C for 2.25 hours. K ₂ CO ₃ (4.86 g, 35.17 mmol) was added in one portion and the reaction mixture was allowed to stir for 20 minutes before warming to room temperature. The reaction mixture was then immersed in a water bath and water (60 ml) was added carefully (foaming occurred) followed by 2M NaOH (5 ml). The reaction mixture was stirred for a further 10 minutes, then the layers were separated. The aqueous layer was extracted with DCM (2 x 50 ml). The combined organic layers were dried (MgSO4), filtered and evaporated to give the title compound (10.3g) as an orange oil. The crude product was passed to the next step without further purification.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=5.14 (s, 1H), 4.72 (ddt, J=10.3, 7.6, 1.2 Hz, 1H), 4.47. (Dd, J=8.7, 7.7 Hz, 1H), 4.39 (dd, J=10.6, 8.8 Hz, 1H), 3.78 (s, 3H), 3.49-3. 36 (m, 2H), 2.48 (td, J=6.2, 1.2Hz, 2H), 1.42 (s, 9H)
HPLCMS (Method A): [m/z]: 273 [M+H] ^+.
Methyl 2-({[(tert-butoxy)carbonyl]amino}methyl)-4,5-dihydro-1,3-oxazole-4-carboxylate (226)

In a similar manner to general procedure 14 methyl 2-(2-{[(tert-butoxy)carbonyl]amino}acetamido)-3-hydroxypropanoate (224) (2.5 g, 7 ml) in DCM (70 ml). .42 mmol) and DAST (1.18 ml, 8.9 mmol) gave the title compound (2.02 g, quantitative) as a yellow oil.

1H-NMR (CDCl ₃ , 250 MHz): d[ppm]=5.12 (s, 1H), 4.86-4.68 (m, 1H), 4.62-4.42 (m, 2H), 4.11-3.89 (m, 2H), 3.82 (s, 3H), 1.44 (s, 9H)
HPLCMS (Method A): [m/z]: 258.95 [M+H] ^+.
General Procedure 15: Methyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-oxazole-4-carboxylate (227).

Bromo(trichloro)methane (10.4 ml, 105.56 mmol) was cooled to 0° C. under nitrogen methyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-4,5-dihydro-1. , 3-Oxazole-4-carboxylate (225) (93.2%, 10.28 g, 35.19 mmol) was added to a solution in anhydrous DCM (300 ml). DBU (15.75 ml, 105.56 mmol) was added dropwise, the mixture was allowed to warm to room temperature and stirred for 2.5 hours. Saturated aqueous citric acid solution (25 ml) was added, followed by water (100 ml). The reaction mixture was vigorously stirred for 10 minutes. The layers were separated and the aqueous layer was extracted with DCM (3 x 100 ml). The organic layer was dried (MgSO4), filtered and evaporated to give a dark brown oil (14.6g). The crude oil was dry loaded onto silica using MeOH (200 ml). The crude material was filtered through a silica plug [gradient elution with heptane (2×500 ml), 25% EtOAc/heptane (2×500 ml) and 50% EtOAc/heptane (11×500 ml) to give the title compound (8.63 g). Obtained as a yellow oil, which solidified on standing.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.16 (s, 1H), 4.99 (s, 1H), 3.90 (s, 3H), 3.57 (q, J= 6.0 Hz, 2H), 2.99 (t, J=6.3 Hz, 2H), 1.40 (s, 9H)
HPLC MS (Method A): [m/z]: 293.0 [M+Na] ^+.
Methyl 2-({[(tert-butoxy)carbonyl]amino}methyl)-4,5-dihydro-1,3-oxazole-4-carboxylate (228)

In a manner similar to general procedure 15 methyl 2-({[(tert-butoxy)carbonyl]amino}methyl)-4,5-dihydro-1,3-oxazole-4-carboxylate (in DCM (75 ml) ( 226) (2.02 g, 7.43 mmol), DBU (3.33 ml, 22.29 mmol) and bromo(trichloro)methane (2.2 ml, 22.29 mmol) with elution gradient 0-100% TBME/heptane. After purification by flash column chromatography, the title compound (1.04 g, 55%) was obtained as a colorless oil.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.19 (s, 1H), 5.19 (br.s, 1H), 4.49 (d, J=5.5 Hz, 2H), 3.92 (s, 3H), 1.45 (s, 9H)
HPLC MS (Method A): [m/z]: 278.95 [M+Na] ^+.
2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-oxazole-4-carboxylic acid (229)

In a similar manner using general procedure 5 LiOH (1.02 g, 42.76 mmol) and methyl 2-(2-{[(tert-butoxy)carbonyl]amino} in THF (100 ml) and water (25 ml). Ethyl)-1,3-oxazole-4-carboxylate (227) (97%, 6.62 g, 23.76 mmol) gave the title compound (4.8 g, 79%) as an off-white powder.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.62 (s, 1H), 6.94 (t, J=5.4 Hz, 1H), 3.31 to 3.26 (m, 2H, partially obscured by HOD peak), 2.87 (t, J=6.8Hz, 2H), 1.35 (s, 9H).
HPLC MS (Method A): [m/z]: 278.9 [M+Na] ^+.
2-({[(tert-Butoxy)carbonyl]amino}methyl)-1,3-oxazole-4-carboxylic acid (230)

In a manner similar to General Procedure 5, methyl 2-({[(tert-butoxy)carbonyl]amino}methyl)-4,5-dihydro-1,3-oxazole-4 in THF/water (20 ml/5 ml). -Carboxylate (228) (1.04 g, 4.06 mmol) and LiOH (0.15 g, 6.09 mmol) gave the title compound (1.07 g, quantitative) as an off-white solid.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.29 (s, 1H), 5.39 (br.s, 1H), 4.54 (d, J=4.9 Hz, 2H), 1.47 (s, 9H)
HPLC MS (Method A): [m/z]: 265 [M+Na] ^+.
tert-Butyl N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-oxazol-2-yl)ethyl]carbamate (231)

In a similar manner using general procedure 6, 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-oxazole-4-carboxylic acid in THF/water (100 ml/40 ml). (229) (3.78 g, 14.75 mmol), HATU (6.17 g, 16.23 mmol), (DIPEA) (8.48 ml, 48.68 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride After purification by flash column chromatography (eluting with gradient 0-100% EtOAc/heptane) with salt (A2) (2.94 g, 14.75 mmol) the title compound (4.83 g, 87%) was a yellow glassy solid. Was obtained as.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.51 (s, 2H), 8.40 (d, J=4.4 Hz, 1H), 7.70 (t, J=9. 3 Hz, 1 H), 7.45 to 7.37 (m, 1 H), 6.98 (t, J=5.5 Hz, 1 H), 4.62 (d, J=5.5 Hz, 2 H), 3. 32-3.28 (m, 2H, signal partially obscured by HOD peak), 2.90 (t, J=6.7Hz, 2H), 1.35 (s, 9H).
HPLCMS (Method A): [m/z]: 365.0 [M+H] ^+.
tert-Butyl N-(2-{4-[(pyridin-2-ylmethyl)carbamoyl]-1,3-oxazol-2-yl}ethyl)carbamate (232)

In a similar manner using general procedure 6, 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-oxazole-4-carboxylic acid (229) (in DMF (65 ml). Flash column chromatography with 4 g, 15.61 mmol), DIPEA (5.44 ml, 31.22 mmol), HATU (8.9 g, 23.41 mmol), pyridin-2-ylmethanamine (2.41 ml, 23.41 mmol). After purification by chromatography (gradient 0-100% EtOAc/heptane elution), the title compound (6.03 g) was obtained as a yellow viscous oil.

1H-NMR (DMSO-d6, 250MHz): d[ppm]=8.74(t, J=5.9Hz, 1H), 8.54-8.48(m, 2H), 7.75(td, J=7.7, 1.8 Hz, 1H), 7.32-7.22 (m, 2H), 6.98 (s, 1H), 4.52 (d, J=6.0 Hz, 2H), 3.29 (d, J=6.5 Hz, 2H), 2.90 (t, J=6.7 Hz, 2H), 1.34 (s, 9H)
HPLC MS (Method A): [m/z]: 347.1 [M+H] ^+.
tert-Butyl N-[2-(4-{[(3-chloropyridin-2-yl)methyl]carbamoyl}-1,3-oxazol-2-yl)ethyl]carbamate (233)

In a similar manner to General Procedure 6, 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-oxazole-4-carboxylic acid (229) (295 mg, in DMF (10 ml). 0.76 mmol, 66%), (3-chloropyridin-2-yl)methanamine dihydrochloride (246 mg, 1.14 mmol), TEA (0.1 ml, 0.76 mmol) and HATU (0.43 g, 1.14 mmol). ), after purification by flash column chromatography (eluting with a gradient of 0-10% MeOH/DCM) to give the title compound (202 mg, 59%, 85% purity) as a yellow oil.

1H-NMR (DMSO-d6, 250MHz): d[ppm]=8.58-8.45 (m, 2H), 7.96 (dd, J=8.1, 1.4Hz, 1H), 7. 40 (dd, J=8.1, 4.7 Hz, 1H), 7.00 (t, J=6.2 Hz, 1H), 4.65 (d, J=5.4 Hz, 2H), 2.97. -2.86 (m, 4H), 1.35 (s, 9H)
HPLC MS (Method A): [m/z]: 381.05 [M+H] ^+.
tert-Butyl N-[(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-oxazol-2-yl)methyl]carbamate (234)

In a similar manner to General Procedure 6, 2-({[(tert-butoxy)carbonyl]amino}methyl)-1,3-oxazole-4-carboxylic acid (230) in THF (15 ml) and DMF (6 ml). (0.5 g, 2.06 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (0.41 g, 2.06 mmol), DIPEA (1.19 ml, 6.81 mmol) and HATU( 0.86 g, 2.27 mmol) afforded the title compound (0.744 g, 98%) as a colorless oil after purification by flash chromatography using an elution gradient 0-100% EtOAc/heptane.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.56 (s, 1H), 8.51 (t, J=5.2 Hz, 1H), 8.38 (d, J=4. 6 Hz, 1 H), 7.73-7.65 (m, 1 H), 7.55 (t, J=5.8 Hz, 1 H), 7.44-7.37 (m, 1 H), 4.65- 4.59 (m, 2H), 4.29 (d, J=5.9Hz, 2H), 1.39 (s, 9H)
HPLCMS (Method A): [m/z]: 351.0 [M+H] ^+.
2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide dihydrochloride (235)

In a similar manner using general procedure 2 tert-butyl N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-oxazol-2-yl) Ethyl]carbamate (231) (4.83 g, 12.86 mmol), 4M HCl in 1,4-dioxane (50 ml) and DCM (80 ml) gave the title compound (4.61 g) as an off-white solid.

1H-NMR (DMSO-d6, 500MHz): d[ppm]=8.71(t, J=5.8Hz, 1H), 8.59(s, 1H), 8.42-8.36(m, 1H), 8.13 (br.s, 3H), 7.76-7.68 (m, 1H), 7.46-7.39 (m, 1H), 4.64 (dd, J=5. 8, 1.4 Hz, 2H), 3.25 (app.q, J=6.1 Hz, 2H), 3.20-3.14 (m, 2H)
HPLC MS (Method F): [m/z]: 265.1 [M+H] ^+.
2-(2-Aminoethyl)-N-(pyridin-2-ylmethyl)-1,3-oxazole-4-carboxamide dihydrochloride (236)

In a similar manner using General Procedure 2 tert-butyl N-(2-{4-[(pyridin-2-ylmethyl)carbamoyl]-1,3-oxazol-2-yl}ethyl)carbamate (in MeOH. 232) (90%, 6.03 g, 15.68 mmol), 12M HCl (26.13 ml) gave the title compound (5.78 g) as a cream foam.

1H-NMR (Methanol-d4, 250MHz): d [ppm] = 8.80 (dd, J = 5.9, 0.8Hz, 1H), 8.62 (td, J = 8.0, 1.6Hz). , 1H), 8.44 (s, 1H), 8.10 (d, J=7.8 Hz, 1H), 8.01 (t, J=6.3 Hz, 1H), 4.93 (s, 2H). ), 3.51-3.43 (m, 2H), 3.26 (t, J=6.4Hz, 2H).
HPLC MS (Method A): [m/z]: 246.9 [M+H] ^+.
2-(2-Aminoethyl)-N-[(3-chloropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide dihydrochloride (237)

In a similar manner using general procedure 2 tert-butyl N-[2-(4-{[(3-chloropyridin-2-yl)methyl]carbamoyl}-1,3-oxazol-2-yl) Ethyl]carbamate (233) (85%, 202 mg, 0.45 mmol), MeOH (5 ml) and 4M HCl in dioxane (1.65 ml) gave the title compound (125 mg, 62%) as a brown solid.

¹ H NMR (DMSO-d6, 500 MHz): d[ppm]=8.67 (t, J=5.6 Hz, 1H), 8.61 (s, 1H), 8.52 (dd, J=4. 7, 1.4 Hz, 1H), 8.15 (s, 3H), 7.96 (dd, J=8.1, 1.4 Hz, 1H), 7.40 (dd, J=8.1, 4) .7 Hz, 1H), 4.67 (d, J=5.6 Hz, 2H), 3.29-3.23 (m, 2H), 3.21-3.16 (m, 2H).
HPLCMS (Method A): [m/z]: 281.1 [M+H] ^+.
2-(Aminomethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide dihydrochloride (238)

In a manner similar to general procedure 2, tert-butyl N-[(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-oxazol-2-yl in DCM (20 ml). ) Methyl]carbamate (234) (744 mg, 2.02 mmol) and 4M HCl in 1,4-dioxane (15 ml) gave the title compound (668 mg, quantitative) as a white solid.

1H-NMR (DMSO-d6, 500MHz): d [ppm] = 8.79 (s, 1H), 8.73 (br.s, 3H), 8.54 (t, J = 5.6Hz, 1H). , 8.39 (d, J=4.7 Hz, 1H), 7.80-7.68 (m, 1H), 7.49-7.38 (m, 1H), 4.66 (d, J=). 4.6Hz, 2H), 4.32 (t, J=5.5Hz, 2H)
HPLCMS (Method F): [m/z]: 251.1 [M+H] ^+.
2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3 -Oxazole-4-carboxamide trihydrochloride (Example compound No. 127)

In a similar manner to general procedure 8 at room temperature overnight 2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole in MeCN (30 ml). -4-Carboxamide dihydrochloride (235) (1 g, 2.97 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (0.63 g, 3.26 mmol) and DBU (1.5 ml, 10.08 mmol) gave a crude intermediate which was further reacted under nitrogen at 80° C. for 3 hours with iron powder (0.5 g) in AcOH (10 ml). The crude material was purified by basic preparative HPLC, followed by further flash column chromatography (gradient eluting with 0-30% MeOH in DCM) to give 2-(2-{[2-(1H-1,3-benzodiene). Azol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazol-4-carboxamide was obtained. The free base was dissolved in MeOH (10 ml) and treated with 12M hydrogen chloride (1.5 ml). The solvent was then rigorously evaporated under vacuum to give the title compound (333 mg, 22%) as a white solid.

1H-NMR (D ₂ O, 500 MHz): d[ppm]=8.34-8.30 (m, 2H), 7.86 (ddd, J=9.6, 8.7, 1.2 Hz, 1H ), 7.74-7.69 (m, 2H), 7.62-7.57 (m, 1H), 7.57-7.52 (m, 2H), 3.74-3.6.6 (m). , J=4.3 Hz, 4 H), 3.64 (t, J=6.7 Hz, 2 H), 3.33 (t, J=6.7 Hz, 2 H)
HPLC MS (method C): [m/z]: 409.1 [M+H] ^+.
2-(2-{bis[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1, 3-Oxazole-4-carboxamide tetrahydrochloride (Example compound No. 128)

In a manner similar to General Procedure 7, DMF (5 ml) 2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide dihydrochloride. By salt (Example Compound #127) (305 mg, 0.9 mmol), 2-(2-chloroethyl)-1H-1,3-benzodiazole hydrochloride (216 mg, 1 mmol) and DIPEA (3.15 ml, 18 mmol). After purification by basic preparative HPLC, the title compound free base was obtained. Treatment of the free base with 12M HCl (0.5ml) in MeOH (5ml) gave the title compound as the tetrahydrochloride salt (5mg, 0.8%) as a brown residue.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.56-8.52(m,1H),8.45(s,1H),8.21-8.15(m,1H) , 7.90-7.84 (m, 2H), 7.84-7.77 (m, 3H), 7.69-7.60 (m, 3H), 7.58 (ddd, J=8. 2,7.4,0.6 Hz, 1H), 5.32-5.22 (m, 2H), 4.90 (s, 2H), 4.17-4.11 (m, 2H), 4. 02-3.94 (m, 2H), 3.93-3.86 (m, 2H), 3.78 (t, J = 6.3Hz, 2H), 3.48 (t, J = 6.3Hz). , 2H)
HPLC MS (Method C): [m/z]: 553.2 [M+H] ^+.
2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-(pyridin-2-ylmethyl)-1,3-oxazole-4-carboxamide Trihydrochloride (Example Compound No. 171)

In a similar manner using general procedure 8, 2-(2-aminoethyl)-N-(pyridin-2-ylmethyl)-1,3-oxazole-4-carboxamide dihydrochloride (236 in MeCN (30 ml). ) (86%, 1.2 g, 3.25 mmol), DBU (1.46 ml, 9.76 mmol) and N-(2-nitrophenyl)prop-2-enamide (D) (0.69 g, 3.58 mmol). Gave the crude intermediate which was further reacted with iron powder (0.52 g) in AcOH (10 ml) to give the title compound (0.22 g, 12%) as a light brown solid.

1H-NMR (D ₂ O), 500 MHz: d[ppm]=8.72 (d, J=5.8 Hz, 1H), 8.54 (td, J=8.0, 1.5 Hz, 1H) , 8.46 (s, 1H), 8.00-7.94 (m, 2H), 7.81 (dt, J=6.2, 3.2Hz, 2H), 7.63 (dt, J= 6.2, 3.3 Hz, 2H), 4.88 (s, 2H), 3.83-3.70 (m, 6H), 3.43 (t, J = 6.9Hz, 2H).
HPLCMS (Method C): [m/z]: 391.2 [M+H] ^+.
2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-chloropyridin-2-yl)methyl]-1,3 -Oxazole-4-carboxamide (Example compound 173)

In a similar manner using general procedure 8, 2-(2-aminoethyl)-N-[(3-chloropyridin-2-yl)methyl]-1,3-oxazole-4-in MeCN (5 ml). Carboxamide dihydrochloride (237) (75%, 120 mg, 0.25 mmol), DBU (76 μl, 0.51 mmol) and N-(2-nitrophenyl)prop-2-enamide (D) (48 mg, 0.25 mmol). To give a crude intermediate which was further reacted with iron powder (36.9 mg) in AcOH (2 ml) to give the title compound (4.6 mg, 3%) as a transparent film after purification by basic preparative HPLC. Was obtained as.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.44 (dd, J=4.7, 1.4Hz, 1H), 8.28 (s, 1H), 7.86 (dd, J=8.1, 1.4 Hz, 1H), 7.47-7.41 (m, 2H), 7.33 (dd, J=8.1, 4.8 Hz, 1H), 7.19-7. .14 (m, 2H), 4.70 (s, 2H), 3.18-3.04 (m, 8H)
HPLCMS (Method C): [m/z]: 425.2 [M+H] ^+.
2-({[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}methyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole -4-carboxamide (Example compound No. 206)

2-(Aminomethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide dihydrochloride in MeCN (10 ml) in a manner similar to general procedure 8. The crude intermediate was prepared with (238) (300 mg, 0.93 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (196 mg, 1.02 mmol) and DBU (471.1 μl, 3.16 mmol). Obtained, which was further reacted with iron powder (156 mg, 2.79 mmol) in AcOH (5 ml) after purification by basic preparative HPLC, followed by flash chromatography using an elution gradient 2-20% MeOH/DCM. , The title compound (20 mg, 27%) was obtained as a white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.15 (s, 1H), 8.57 (s, 1H), 8.53 (t, J=5.6 Hz, 1H), 8 .38 (dt, J=4.6, 1.3 Hz, 1H), 7.70 (m, 1H), 7.51 (d, J=6.9 Hz, 1H), 7.41 (m, 2H) , 7.15-7.07 (m, 2H), 4.62 (dd, J=5.6, 1.3 Hz, 2H), 3.92 (s, 2H), 3.04-2.99( m, 2H), 2.98-2.94 (m, 2H)
HPLC MS (Method C): [m/z]: 395.1 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4- Carboxamide trihydrochloride (Example compound No. 126)

In a similar manner using general procedure 3 at room temperature for 16 hours 2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3 in DCM (10 ml). -Oxazole-4-carboxamide dihydrochloride (235) (100 mg, 0.3 mmol), 1H-benzimidazole-2-carbaldehyde (43.3 mg, 0.3 mmol), DIPEA (0.207 ml, 1.19 mmol) and The free base compound was obtained after purification by basic preparative HPLC by addition of anhydrous MgSO ₄ (200 mg) followed by NaBH ₄ (17 mg, 0.45 mmol). The residue was redissolved in MeOH (5 ml) and treated with 12M HCl (1 ml) for 30 minutes to give the title compound (64 mg, 42%) as a white hygroscopic solid.

1H-NMR (Methanol-d4,500MHz): d [ppm] = 8.57 (dd, J = 5.4, 0.9Hz, 1H), 8.46 (s, 1H), 8.26-8. 19 (m, 1H), 7.88 (ddt, J=13.4, 8.9, 4.1 Hz, 3H), 7.68 (td, J=6.3, 5.5, 2.1 Hz, 2H), 5.02 (s, 2H), 4.94 (s, 2H), 3.83 (t, J=6.3Hz, 2H), 3.47 (t, J=6.3Hz, 2H)
HPLC MS (Method C): [m/z]: 395.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-(pyridin-2-ylmethyl)-1,3-oxazole-4-carboxamide (Example compound 137) No.)

2-(2-Aminoethyl)-N-(pyridin-2-ylmethyl)-1,3-oxazole-4-carboxamide in MeOH (20 ml) in a similar manner using general procedure 3 for 17 hours at room temperature. Dihydrochloride (236) (430 mg, 1.31 mmol), 1H-benzimidazole-2-carbaldehyde (229 mg, 1.57 mmol) and DIPEA (0.91 ml, 5.23 mmol) followed by NaBH ₄ (74 mg, 1). .96 mmol) was added to give the title compound (380 mg, 77%) as a yellow solid after purification by flash chromatography using a gradient elution of 0-20% MeOH/DCM.

1H-NMR (DMSO-d6, 500MHz): d[ppm]=12.17(s, 1H), 8.72(t, J=5.9Hz, 1H), 8.53-8.46(m, 2H), 7.74 (td, J=7.7, 1.7Hz, 1H), 7.48 (m, 2H), 7.31-7.22 (m, 2H), 7.12 (m, 2H), 4.52 (d, J=6.0 Hz, 2H), 3.95 (s, 2H), 3.03-2.93 (m, 4H)
HPLC MS (Method C): [m/z]: 377.2 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-chloropyridin-2-yl)methyl]-1,3-oxazole-4- Carboxamide (Example Compound No. 141)

In a similar manner to General Procedure 3, 2-(2-aminoethyl)-N-[(3-chloropyridin-2-yl)methyl]-1,3-thiazole in MeOH (4 ml) for 24 hours at room temperature. 4-carboxamide dihydrochloride (237) (118mg, 0.31mmol) , 1H- benzimidazol-2-carbaldehyde (54 mg, 0.37 mmol) and DIPEA (0.216ml, 1.24mmol), NaBH 4 and subsequently (18 mg, 0.46 mmol) was added to give the title compound (51 mg, 40%) as a brown solid after purification by basic preparative HPLC.

1H-NMR (Methanol-d4,500 MHz): d[ppm]=8.41 (dd, J=4.8, 1.4 Hz, 1H), 8.29 (s, 1H), 7.86 (dd, J=8.1, 1.4 Hz, 1H), 7.53-7.49 (m, 2H), 7.34-7.30 (m, 1H), 7.21-7.18 (m, 2H). ), 4.76 (s, 2H), 4.08 (s, 2H), 3.14-3.09 (m, 2H), 3.07-3.03 (m, 2H).
HPLCMS (Method D): [m/z]: 411.2 [M+H] ^+.
2-(2-{[2-(4,5-difluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl) Methyl]-1,3-oxazole-4-carboxamide (Example compound 257)

In a similar manner to General Procedure 8, 2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidediamine in MeCN (10 ml). Hydrochloride (235) (350 mg, 1.04 mmol), N-(2,3-difluoro-6-nitrophenyl)prop-2-enamide (K10) (250 mg, 1.10 mmol) and DBU (465 μl, 3.11 mmol). ) Afforded the intermediate (193 mg) after purification by flash column chromatography (eluting with a gradient 0-20% MeOH/DCM). The intermediate was further reacted with iron powder (88 mg, 1.57 mmol) in AcOH (2 ml), flash column chromatography (eluting with a gradient of 0-30% MeOH/DCM) followed by purification by basic preparative HPLC. Afterwards, the title compound (14 mg, 8%) was obtained as a pale yellow solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.55-8.47 (m, 2H), 8.38 (d, J=4.6 Hz, 1H), 7.74-7. 67 (m, 1H), 7.44-7.36 (m, 1H), 7.23 (dd, J=8.8, 3.6Hz, 1H), 7.17-7.09 (m, 1H). ), 4.61 (d, J=4.8 Hz, 2H), 3.02-2.91 (m, 8H)
HPLC MS (Method G): [m/z]: 445.2 [M+H] ^+.
2-(2-{[2-(4-chloro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl] -1,3-Oxazole-4-carboxamide (Example compound No. 226)

In a similar manner to General Procedure 8, 2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidediamine in MeCN (10 ml). By the hydrochloride salt (235) (340 mg, 1.01 mmol), N-(3-chloro-2-nitrophenyl)prop-2-enamide (H) (245 mg, 1.08 mmol) and DBU (147 μl, 0.98 mmol). The crude intermediate was obtained, which was further reacted with iron powder (81 mg, 1.45 mmol) in AcOH (4 ml) for basic preparative HPLC followed by flash column chromatography (0-40% MeOH/DCM). After purification by gradient elution), the title compound (31 mg, 19%) was obtained as a white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.51 (m, 2H), 8.38 (dt, J=4.6, 1.2 Hz, 1H), 7.70 (ddd, J=10.0, 8.3, 1.2 Hz, 1H), 7.41 (m, 2H), 7.19 (dd, J=7.7, 0.8 Hz, 1H), 7.12 (t). , J=7.7 Hz, 1H), 4.62 (dd, J=5.6, 1.3 Hz, 2H), 3.09-2.95 (m, 8H).
HPLC MS (Method C): [m/z]: 443.1 [M+H] ^+.
N-[(3-fluoropyridin-2-yl)methyl]-2-(2-{[2-(4-methoxy-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl) -1,3-Oxazole-4-carboxamide (Example compound No. 227)

In a manner similar to general procedure 8, 2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidediamine in MeCN (10 ml). Hydrochloride (235) (301 mg, 0.89 mmol), N-(2-methoxy-6-nitrophenyl)prop-2-enamide (I) (198 mg, 0.89 mmol) and DBU (0.4 ml, 2.68 mmol). ) Gave a crude intermediate which was partially purified by flash column chromatography using a gradient elution of 0-10% MeOH in DCM. The intermediate was further reacted with iron powder (86 mg) in AcOH (3 ml) and after purification by basic preparative HPLC followed by flash column chromatography (eluting with a gradient of 0-20% MeOH/DCM), the title compound was obtained. (2 mg, 1%) was obtained as a white solid.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.30 (d, J=4.7 Hz, 1H), 8.26 (s, 1H), 7.60-7.54 (m, 1H). , 7.39-7.32 (m, 1H), 7.09 (t, J=8.0 Hz, 1H), 7.03 (d, 1H), 6.70 (d, J=7.8 Hz, 1H), 4.65 (d, J=1.4 Hz, 2H), 3.93 (s, 3H), 3.22-3.16 (m, 4H), 3.14-3.05 (m, 4H)
HPLC MS (Method G): [m/z]: 439.2 [M+H] ^+.
2-(2-{[2-(4-Fluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl] -1,3-Oxazole-4-carboxamide (Example compound No. 228)

In a similar manner to General Procedure 8, 2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidediamine in MeCN (10 ml). By the hydrochloride salt (235) (200 mg, 0.59 mmol), N-(3-fluoro-2-nitrophenyl)prop-2-enamide (G) (198 mg, 0.89 mmol) and DBU (266 μl, 1.78 mmol). The crude intermediate was obtained, which was partially purified by flash column chromatography using a gradient elution of 0-10% MeOH in DCM. The intermediate was further reacted with iron powder (114 mg) in AcOH (2 ml) and subjected to basic preparative HPLC followed by flash column chromatography (eluting with a gradient of 0-30% MeOH/DCM) and kp-NH flash chromatography. After purification by chromatography (eluting with a gradient of 0-4% MeOH/DCM), the title compound (10 mg, 5%) was obtained as an off-white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.53-8.45 (m, 2H), 8.39-8.35 (m, 1H), 7.72-7.67( m, 1H), 7.42-7.37 (m, 1H), 7.26 (d, J=8.0Hz, 1H), 7.11-7.05 (m, 1H), 6.93- 6.88 (m, 1H), 4.61 (d, J=4.4Hz, 2H), 3.01-2.91 (m, 8H)
HPLC MS (Method G): [m/z]: 427.1 [M+H] ^+.
2-(2-{[2-(7-chloro-4-fluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridine-2- Iyl)methyl]-1,3-oxazole-4-carboxamide (Example compound #247)

In a similar manner to General Procedure 8, 2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidedimedium in MeCN (15 ml). Hydrochloride (235) (300 mg, 0.89 mmol), N-(6-chloro-3-fluoro-2-nitrophenyl)prop-2-enamide (K2) (272 mg, 0.89 mmol) and DBU (0.398 ml). (2.67 mmol) afforded the crude intermediate which was purified by flash column chromatography using elution gradient 0-15% MeOH in DCM. The intermediate was further reacted with iron powder (145 mg) in AcOH (3 ml) and flash column chromatography (eluting with a gradient of 0-35% MeOH/DCM) followed by kp-NH column chromatography (0-15%). After elution with a gradient of MeOH/DCM) and purification by basic preparative HPLC, the title compound (7 mg, 2%) was obtained as a beige solid.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.34 (d, J=4.7 Hz, 1H), 8.27 (s, 1H), 7.63-7.56 (m, 1H). , 7.42-7.36 (m, 1H), 7.16 (dd, J=8.6, 3.9 Hz, 1H), 6.93 (dd, J=10.2, 8.6 Hz, 1H) ), 4.71 (d, J=1.6 Hz, 2H), 3.16-3.11 (m, 6H), 3.07-3.03 (m, 2H).
HPLCMS (Method D): [m/z]: 461.1 [M+H] ^+.
2-(2-{[2-(4,6-difluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl) Methyl]-1,3-oxazole-4-carboxamide (Example compound 249)

In a similar manner to General Procedure 8, 2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidedimedium in MeCN (15 ml). Hydrochloride (235) (500 mg, 1.48 mmol), N-(2,4-difluoro-6-nitrophenyl)prop-2-enamide (K4) (338 mg, 1.48 mmol) and DBU (0.664 ml, 4). 0.45 mmol) afforded the crude intermediate which was partially purified by flash column chromatography using a gradient of 0-20% MeOH in DCM. The intermediate was further reacted with iron powder (145 mg) in AcOH (4 ml) and flash column chromatography (eluting with a gradient of 0-40% MeOH/DCM) followed by kp-NH flash chromatography (0-5%). After purification by elution with a MeOH/DCM gradient), the title compound (23 mg, 8%) was obtained as an off-white solid.

1H-NMR (DMSO-d6, 500MHz): d[ppm]=8.53-8.46 (m, 2H), 8.41-8.36 (m, 1H), 7.73-7.67( m, 1H), 7.43-7.37 (m, 1H), 7.14 (dd, J=8.9, 2.2Hz, 1H), 6.96 (td, J=10.7, 2) .2 Hz, 1 H), 4.62 (dd, J=5.7, 1.4 Hz, 2 H), 3.02-2.90 (m, 8 H)
HPLC MS (Method G): [m/z]: 445.2 [M+H] ^+.
2-(2-{[2-(5-fluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl] -1,3-Oxazole-4-carboxamide (Example compound No. 250)

2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole in MeCN (30 ml) for 20 hours at room temperature in a manner similar to general procedure 8. -4-Carboxamide dihydrochloride (235) (1.07 g, 2.59 mmol, purity 82%), N-(5-fluoro-2-nitrophenyl)prop-2-enamide (J) (0.54 g, 2 .59 mmol) and DBU (1.28 ml, 8.54 mmol) gave a crude mixture of monoalkylated:bisalkylated (1:1.4) adduct (1.1 g), which was further AcOH (8 ml). ) Medium iron powder (0.52 g) upon flash column chromatography (eluting with a gradient of 0-30% MeOH/DCM) followed by kp-NH flash column chromatography (0-2% MeOH/DCM). After elution with a gradient) followed by flash column chromatography (eluting with a gradient of 0-20% MeOH/DCM) and purification by basic preparative HPLC, the title compound (90 mg, 9%) was obtained as a brown solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.52-8.47 (m, 2H), 8.39-8.36 (m, 1H), 7.72-7.66( m, 1H), 7.46-7.36 (m, 2H), 7.24 (dd, J=9.6, 2.3Hz, 1H), 6.99-6.89 (m, 1H), 4.61 (dd, J=5.7, 1.3 Hz, 2H), 3.02-2.89 (m, 8H)
HPLC MS (Method C): [m/z]: 427.2 [M+H] ^+.
2-(2-{[2-(4,7-difluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl) Methyl]-1,3-oxazole-4-carboxamide (Example compound No. 251)

In a similar manner to General Procedure 8, 2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidedimedium in MeCN (15 ml). Hydrochloride (235) (400 mg, 1.19 mmol), N-(3,6-difluoro-2-nitrophenyl)prop-2-enamide (K6) (316 mg, 1.20 mmol) and DBU (0.53 ml, 3). 0.56) afforded the crude intermediate which was partially purified by flash column chromatography using a gradient elution of 0-20% MeOH in DCM. This intermediate was further reacted with iron powder (230 mg) in AcOH (4 ml) by flash column chromatography (eluting with a gradient of 0-40% MeOH/DCM) followed by kp-NH flash chromatography (0-5). After purification by elution with a gradient of% MeOH/DCM), the title compound (63 mg, 14%) was obtained as an off-white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.52-8.46 (m, 2H), 8.38 (m, 1H), 7.74-7.66 (m, 1H). , 7.44-7.37 (m, 1H), 6.95-6.91 (m, 2H), 4.62 (dd, J=5.6, 1.4Hz, 2H), 3.03-. 2.90 (m, 8H).
HPLC MS (Method G): [m/z]: 445.2 [M+H] ^+.
N-[(3-fluoropyridin-2-yl)methyl]-2-[2-({2-[4-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl]ethyl} Amino)ethyl]-1,3-oxazole-4-carboxamide (Example compound No. 256)

In a similar manner to General Procedure 8, 2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidediamine in MeCN (10 ml). Hydrochloride (235) (300 mg, 0.89 mmol), N-[2-nitro-6-(trifluoromethyl)phenyl]prop-2-enamide (K8) (272 mg, 0.90 mmol) and DBU (398 μl, 2). .67 mmol) afforded the crude intermediate which was partially purified by flash column chromatography using a gradient of 0-10% MeOH in DCM. The intermediate was further reacted with iron powder (177 mg) in AcOH (3 ml) and flash column chromatography (eluted with a gradient of 0-25% MeOH/DCM) followed by kp-NH flash chromatography (0-6%). After purification by elution with a MeOH/DCM gradient) the title compound (99 mg, 26%) was obtained as a yellow solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.53-8.47 (m, 2H), 8.40-8.37 (m, 1H), 7.75 (d, J= 8.0 Hz, 1 H), 7.73-7.67 (m, 1 H), 7.45 (d, J=7.6 Hz, 1 H), 7.43-7.38 (m, 1 H), 7. 28 (t, J=7.8 Hz, 1H), 4.62 (d, J=4.7 Hz, 2H), 3.01 (s, 4H), 3.00-2.93 (m, 4H)
HPLC MS (Method G): [m/z]: 477.4 [M+H] ^+.
2-(2-{[2-(4-Fluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-(pyridin-2-ylmethyl)-1,3-oxazole -4-carboxamide (Example compound No. 236)

In a manner similar to general procedure 8, 2-(2-aminoethyl)-N-(pyridin-2-ylmethyl)-1,3-oxazole-4-carboxamide dihydrochloride (236) (236) (in MeCN (15 ml)). 350 mg, 0.95 mmol), N-(3-fluoro-2-nitrophenyl)prop-2-enamide (G) (206 mg, 0.95 mmol), DBU (1.0 ml, 2.85 mmol) to give a crude mixture. It was partially purified by flash column chromatography (eluting with a gradient of 0-15% MeOH/DCM). The mixture was further reacted with iron powder (136 mg) in AcOH (4 ml), flash column chromatography (eluting with a gradient of 0-40% MeOH/DCM), kp-NH flash column chromatography (0-10% MeOH/ After elution with a gradient of DCM) and purification by basic preparative HPLC, the title compound (9 mg, 4%) was obtained as a light brown solid.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.52-8.47 (m, 1H), 8.28 (s, 1H), 7.80 (td, J=7.7, 1. 8 Hz, 1 H), 7.39 (d, J=7.9 Hz, 1 H), 7.34-7.30 (m, 1 H), 7.28 (d, J=8.0 Hz, 1 H), 7. 19-7.10 (m, 1H), 6.96-6.88 (m, 1H), 4.65 (s, 2H), 3.17-3.08 (m, 6H), 3.08-. 3.02 (m, 2H)
HPLC MS (Method D): [m/z]: 409.1 [M+H] ^+.
Methyl 2-(3-{[(tert-butoxy)carbonyl]amino}propanamide)-3-hydroxybutanoate (315)

In a manner similar to general procedure 13, L-threonine methyl ester hydrochloride (1:1) (11 g, 64.9 mmol) in DCM (250 ml), N-(tert-butoxycarbonyl)-β-alanine (12. After purification by flash column chromatography (eluting with a gradient of 0-100% EtOAc/heptane) by 3 g, 64.9 mmol), TEA (9.94 ml, 71.3 mmol) and DCC (14.7 g, 71.3 mmol). , The title compound (16.4 g, 72.4%, purity 87%) was obtained as a viscous yellow oil.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=6.35 (s, 1H), 5.12 (s, 1H), 4.59 (dd, J=8.8, 2.5 Hz, 1H ), 4.36 (qd, J=6.4, 2.5 Hz, 1H), 3.78 (s, 3H), 3.45 (q, J=5.9 Hz, 2H), 2.57-2. .46 (m, 2H), 1.43 (s, 9H), 1.23 (d, J=6.4Hz, 3H)
HPLCMS (Method A): [m/z]: 291.05 [M+H] ^+.
Methyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-4,5-dihydro-1,3-oxazole-4-carboxylate (316)

In a manner similar to general procedure 14, methyl 2-(3-{[(tert-butoxy)carbonyl]amino}propanamide)-3-hydroxybutanoate (315) (1 g, 2) in anhydrous DCM (25 ml). .87Mmol, purity 87%), DAST (0.45ml, 3.44mmol) and _K 2 _CO 3 (0.79g, by 5.73 mmol), eluting with a gradient flash column chromatography (0 to 100% EtOAc / heptane After purification by (), the title compound (0.61 g, 67%) was obtained as a pale yellow oil.

1H-NMR (CDCl ₃ , 250 MHz): d[ppm]=5.22 (br s, 1H), 4.87 (dq, J=9.9, 6.3 Hz, 1H), 4.76 (dt, J=10.1, 1.2 Hz, 1H), 3.76 (s, 3H), 3.52-3.37 (m, 2H), 2.53-2.44 (m, 2H), 1. 44 (s, 9H), 1.29 (d, J=6.3Hz, 3H)
Methyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-1,3-oxazole-4-carboxylate (317)

In a similar manner to general procedure 15 methyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-4,5-dihydro-1,3-oxazole in DCM (15 ml). Flash column chromatography by -4-carboxylate (316) (0.61 g, 1.98 mmol), bromo(trichloro)methane (0.59 ml, 5.95 mmol) and DBU (0.89 ml, 5.95 mmol) ( After purification by elution with a gradient of 0-100% EtOAc/heptane) the title compound (0.42 g, 71%) was obtained as a dark orange oil which solidified on standing.

_{1H-NMR (CDCl 3, 250MHz} ): d [ppm] = 4.94 (s, 1H), 3.90 (s, 3H), 3.55 (q, J = 6.2Hz, 2H), 2. 93 (t, J=6.3 Hz, 2H), 2.59 (s, 3H), 1.42 (s, 9H)
HPLCMS (Method A): [m/z]: 284.95 [M+H] ^+.
2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-1,3-oxazole-4-carboxylic acid (318)

In a manner similar to General Procedure 5, methyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-1,3-oxazole- in THF (8 ml) and water (2 ml). 4-Carboxylate (317) (0.42g, 1.42mmol), LiOH (0.067g, 2.84mmol) gave the title compound (0.4g, 98%) as a pale orange oil which was left to stand. Then it solidified.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=12.72 (s, 1H), 6.90 (t, J=5.5 Hz, 1H), 3.25 (d, J=6. 2 Hz, 2 H), 2.79 (t, J=6.9 Hz, 2 H), 1.34 (s, 9 H) [CH ₃ peak obscured by DMSO peak]
HPLCMS (Method A): [m/z]: 293.00 [M+Na] ^+.
tert-Butyl N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-5-methyl-1,3-oxazol-2-yl)ethyl]carbamate (319)

In a similar manner to General Procedure 6, 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-1,3-oxazole-4-carboxylic acid (318) in DMF (6 ml). ) (0.4 g, 1.39 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (0.415 g, 2.09 mmol), DIPEA (0.8 ml, 4.59 mmol) and HATU. After purification by flash column chromatography (eluting with a gradient of 0-100% EtOAc/Heptane) by (0.79 g, 2.09 mmol), the title compound (0.653 g, 79%, 64% purity) was obtained as a yellow oil. Was obtained.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.44-8.30 (m, 2H), 7.75-7.64 (m, 1H), 7.46-7.34( m, 1H), 6.97 (brs, 1H), 4.60 (d, J=4.2 Hz, 2H), 3.34-3.24 (m, 2H), 2.83 (t, J). =6.8 Hz, 2H), 1.35 (s, 9H)
HPLCMS (Method A): [m/z]: 379.05 [M+H] ^+.
2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-methyl-1,3-oxazole-4-carboxamide dihydrochloride (320)

In a manner similar to general procedure 2, tert-butyl N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-5-methyl-1,3 in MeOH (10 ml). -Oxazol-2-yl)ethyl]carbamate (319) (0.65 g, 1.10 mmol, 64% purity) and 12M HCl (1.16 ml, 11.04 mmol) gave the title compound (0.51 g, 76% purity). ) Was obtained as a hygroscopic off-white solid. The compound was used in the next step without further purification.

1H-NMR (MeOD, 250 MHz): d[ppm]=8.55 (dd, J=5.3, 1.0 Hz, 1H), 8.22 to 8.10 (m, 1H), 7.86 to. 7.75 (m, 1H), 3.70 (dd, J=11.2, 7.3 Hz, 3H), 3.43 (t, J=6.5 Hz, 2H), 3.17 (t, J = 6.5 Hz, 2H), 2.58 (s, 3H) [CH ₂ peak obscured by H ₂ O]
HPLC MS (Method A): [m/z]: 279.2 [M+H] ^+.
N-[(3-fluoropyridin-2-yl)methyl]-5-methyl-2-[2-({2-[(2-nitrophenyl)carbamoyl]ethyl}amino)ethyl]-1,3-oxazole -4-carboxamide (Example compound No. 230)

In a similar manner to general procedure 8 for 20 hours at room temperature 2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-methyl-1 in MeCN (15 ml). , 3-Oxazole-4-carboxamide dihydrochloride (320) (0.51 g, 1.11 mmol, purity 76%), N-(2-nitrophenyl)prop-2-enamide (D) (0.4 g, 2 .09 mmol) and DBU (0.69 ml, 4.59 mmol) gave a mixture of mono-alkylated:bis-alkylated (1:3.6) adducts which was further iron powder in AcOH (3.5 ml). Reaction with (0.31 g) flash column chromatography (eluting with a gradient of 0-30% MeOH/DCM) followed by flash column chromatography (KP-NH, eluting with a gradient of 0-5% MeOH/DCM). ) And final purification by flash column chromatography (eluting with a slow gradient of 0-30% MeOH/DCM) to give the title compound (0.12 g, 20%) as a pale green solid.

1H-NMR (MeOD, 250 MHz): d[ppm]=8.33-8.30 (d, J=4.7 Hz, 1H), 7.60-7.54 (m, 1H), 7.48-. 7.40 (m, 2H), 7.38-7.33 (m, 1H), 7.18-7.14 (m, 2H), 4.65 (d, J=1.6Hz, 2H), 3.15-3.07 (m, 6H), 2.97 (t, J=6.6Hz, 2H), 2.52 (s, 3H)
HPLC MS (Method C): [m/z]: 423.1 [M+H] ^+.
General Scheme 12 above:
2-(2-{[2-(5-cyano-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl] -1,3-Oxazole-4-carboxamide (Example compound No. 265)

In a manner similar to general procedure 8, 2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidediamine in MeCN (12 ml). Hydrochloride (235) (400 mg, 1.19 mmol), N-(4-cyano-2-nitrophenyl)prop-2-enamide (K12) (325 mg, 1.49 mmol) and DBU (0.53 ml, 3.56 mmol). ) Gave a crude intermediate which was further reacted with iron powder (239 mg, 4.28 mmol) in AcOH (4 ml) and purified by flash column chromatography (eluting with a gradient of 0-20% MeOH/DCM). Afterwards, the title compound (24 mg, 5%) was obtained as a brown solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.51-8.46 (m, 2H), 8.39-8.36 (m, 1H), 8.01-7.95( m, 1H), 7.72-7.67 (m, 1H), 7.63-7.59 (m, 1H), 7.50 (dd, J=8.3, 1.5Hz, 1H), 7.42-7.38 (m, 1H), 4.63-4.59 (m, 2H), 3.02-2.91 (m, 8H)
HPLCMS (Method B): [m/z]: 434.2 [M+H] ^+.
General Scheme 13 above:
Methyl 1-(cyanomethyl)-1H-1,2,4-triazole-3-carboxylate (239)

Methyl 1H-1,2,4-triazole-3-carboxylate (5 g, 39.34 mmol) and 2-bromoacetonitrile (2.7 ml, 39.34 mmol) in DMF (45 ml) were stirred for 5 minutes. K ₂ CO ₃ (5.44 g, 39.34 mmol) was added and the reaction was stirred at room temperature for 23 hours. The solvent was evaporated under vacuum, water (20 ml) was added and the aqueous layer was extracted with EtOAc (8 x 50 ml). The combined organic layers were washed with 5% aqueous LiCl solution (2 x 20 ml), brine (2 x 20 ml), dried (MgSO4), filtered and evaporated to give a mixture of regioisomers (1.5:1). ) Was obtained as a dark brown oil (5.27 g). The crude material was purified by flash column chromatography (eluting with a gradient of 10-100% EtOAc/heptane) to give the title compound (3.5 g, 45%) as a light brown oil which solidified on standing.

1H-NMR (DMSO-d6, 250MHz): d[ppm]=8.30 (s, 1H), 5.79 (s, 2H), 3.94 (s, 3H).
Methyl 1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1H-1,2,4-triazole-3-carboxylate (240)

Methyl 1-(cyanomethyl)-1H-1,2,4-triazole-3-carboxylate (239) (1 g, 6.02 mmol) in EtOH (30 ml), di-tert-butyl dicarbonate (2.63 g, 12). 0.04 mmol) and TEA (1.7 ml, 12.04 mmol) were stirred for 5 minutes, and then 10% palladium carbon (128 mg, 0.602 mmol) was added. The reaction was stirred under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through celite and the residue washed with EtOH (30 ml). Evaporation of the filtrate gave a brown oil which started to crystallize on standing (1.95 g). Purification by flash column chromatography (eluting with a gradient of 0-100% EtOAc/heptane) provided the title compound (1.35 g, 69.7%) as a light brown solid.

1H-NMR (CDCl ₃ , 250 MHz): d [ppm] = 8.13 (s, 1H), 4.69 (br s, 1H), 4.40 (t, J = 5.6 Hz, 2H), 4 0.00 (s, 3H), 3.60 (app q, J=5.9Hz, 2H), 1.42 (s, 9H)
HPLCMS (Method A): [m/z]: 271.1 [M+H] ^+.
1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1H-1,2,4-triazole-3-carboxylic acid (241)

In a similar manner using general procedure 5 LiOH (0.11 g, 4.72 mmol) and methyl 1-(2-{[(tert-butoxy)carbonyl]amino} in THF (20 ml)/water (5 ml). Ethyl)-1H-1,2,4-triazole-3-carboxylate (240) (0.87 g, 2.69 mmol) gave the title compound (0.71 g, 100%) as a cream solid. The compound was used in the next step without further purification.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.54 (s, 1H), 6.97 (br s, 1H), 4.26 (t, J=5.9 Hz, 2H), 3.34 (app q, J=5.8Hz, 2H), 1.34 (s, 9H), obscured by H ₂ O peak
HPLC MS (Method A): [m/z]: 257.05 [M+H] ^+.
tert-Butyl N-[2-(3-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1H-1,2,4-triazol-1-yl)ethyl]carbamate (242)

1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1H-1,2,4-triazole-3-carboxylic acid in DMF (10 ml) in a similar manner using general procedure 6. (241) (0.5 g, 1.95 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (0.58 g, 2.93 mmol), DIPEA (1.7 ml, 9.76 mmol). , HATU (1.11 g, 2.93 mmol) by flash column chromatography (eluting with a gradient of 0-10% MeOH/DCM) followed by a second flash column chromatography (eluting with 0-10% gradient). After purification, the title compound (0.55g, 76%) was obtained as an off-white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.74 (t, J=5.6 Hz, 1H), 8.57 (s, 1H), 8.39 (d, J=4. 6 Hz, 1 H), 7.78-7.63 (m, 1 H), 7.42 (dt, J=8.6, 4.4 Hz, 1 H), 7.00 (s, 1 H), 4.64 ( d, J=4.7 Hz, 2H), 4.28 (t, J=5.9 Hz, 2H), 3.36 (app q, J=5.9 Hz, 2H), 1.35 (s, 9H).
HPLCMS (Method A): [m/z]: 365.15 [M+H] ^+.
tert-Butyl N-[2-(3-{[(3-chloropyridin-2-yl)methyl]carbamoyl}-1H-1,2,4-triazol-1-yl)ethyl]carbamate (243)

1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1H-1,2,4-triazole-3-carboxylic acid in DMF (11 ml) in a similar manner using general procedure 6. (241) (0.58 g, 2.26 mmol), (3-chloropyridin-2-yl)methanamine dihydrochloride (0.732 g, 3.4 mmol), HATU (1.29 g, 3.4 mmol), DIPEA( 1971 μl, 11.32 mmol) gave the title compound (0.87 g, 96%) as a brown foam after purification by flash column chromatography eluting with a gradient of 0-10% MeOH/DCM.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.73 (t, J=5.3 Hz, 1H), 8.57 (s, 1H), 8.52 (d, J=4. 4 Hz, 1 H), 7.96 (d, J=8.0 Hz, 1 H), 7.39 (dd, J=8.0, 4.7 Hz, 1 H), 7.00 (s, 1 H), 4. 67 (d, J=5.4 Hz, 2H), 4.28 (t, J=5.9 Hz, 2H), 3.36 (app q, J=6.1 Hz, 2H), 1.35 (s, 9H)
HPLC MS (Method A): [m/z]: 381.05 [M+H] ^+.
1-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-1,2,4-triazole-3-carboxamide dihydrochloride (244)

In a similar manner using General Procedure 2 at 40° C. for 2 hours, 12M HCl (2.48 ml) in MeOH (10 ml) and tert-butyl N-[2-(3-{[(3-fluoropyridine- 2-yl)methyl]carbamoyl}-1H-1,2,4-triazol-1-yl)ethyl]carbamate (242) (0.54g, 1.49mmol) afforded the title compound (0.52g, 100%). Was obtained as an off-white foam. The compound was used in the next step without further purification.

1H-NMR (DMSO-d6, 250MHz): d[ppm]=8.89(t, J=5.6Hz, 1H), 8.70(s, 1H), 8.39(d, J=4. 7 Hz, 1 H), 8.25 (s, 3 H), 7.80-7.67 (m, 1 H), 7.43 (dt, J=8.6, 4.5 Hz, 1 H), 4.66 ( d, J=4.4 Hz, 2H), 4.55 (t, J=5.9 Hz, 2H), 3.32 (q, J=5.6 Hz, 2H)
HPLCMS (Method A): [m/z]: 265.05 [M+H] ⁺
1-(2-aminoethyl)-N-[(3-chloropyridin-2-yl)methyl]-1H-1,2,4-triazole-3-carboxamide dihydrochloride (245)

In a similar manner using General Procedure 2 at 40° C. for 3 hours, 12 M HCl (3.6 ml) in MeOH (15 ml) and tert-butyl N-[2-(3-{[(3-chloropyridine- 2-yl)methyl]carbamoyl}-1H-1,2,4-triazol-1-yl)ethyl]carbamate (243) (0.87g, 2.17mmol) afforded the title compound (0.84g, 99%). Was obtained as a pale orange foam.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.89 (t, J=5.5 Hz, 1H), 8.74 (s, 1H), 8.53 (dd, J=4. 7, 1.3 Hz, 1 H), 8.35 (s, 3 H), 7.99 (dd, J=8.1, 1.4 Hz, 1 H), 7.42 (dd, J=8.1, 4) .7 Hz, 1 H), 4.69 (d, J=5.5 Hz, 2 H), 4.58 (t, J=5.9 Hz, 2 H), 3.33 (q, J=5.8 Hz, 2 H) , 3.17 (s, 1H), 2.69 (s, 1H)
HPLCMS (Method A): [m/z]: 280.95 [M+H] ^+.
1-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1H-1,2,4- Triazole-3-carboxamide (Example compound 169)

In a similar manner using General Procedure 3 at room temperature for 17 hours, 1H-1,3-benzodiazole-2-carbaldehyde (104 mg, 0.71 mmol), 1-(2-amino in MeOH (8 ml). Ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-1,2,4-triazol-3-carboxamide dihydrochloride (244) (200 mg, 0.59 mmol) and DIPEA (0. 41 ml, 2.37 mmol) followed by NaBH ₄ (32 mg, 0.86 mmol) to give the title compound (79 mg, 34%) as a beige solid after purification by basic preparative HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.16 (s, 1H), 8.76 (t, J=5.6 Hz, 1H), 8.65 (s, 1H), 8 .38 (d, J=4.7 Hz, 1H), 7.70 (app t, J=9.3 Hz, 1H), 7.49 (br d, J=38.6 Hz, 2H), 7.40- 7.43 (m, 1H), 7.12 (d, J = 3.7Hz, 2H), 4.64 (d, J = 5.5Hz, 2H), 4.34 (t, J = 6.0Hz) , 2H), 3.92 (s, 2H), 3.02 (t, J=5.9Hz, 2H)
HPLC MS (Method C): [m/z]: 395.2 [M+H] ^+.
1-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-1 ,2,4-triazole-3-carboxamide (Example compound No. 181)

In a similar manner using general procedure 8 for 16 h at room temperature DBU (0.39 ml, 2.58 mmol) in MeCN (14 ml), 1-(2-aminoethyl)-N-[(3-fluoropyridine). 2-yl)methyl]-1H-1,2,4-triazole-3-carboxamide dihydrochloride (244) (300 mg, 0.86 mmol) and N-(2-nitrophenyl)prop-2-enamide (D ) (165 mg, 0.86 mmol) afforded the crude intermediate (0.364 g) as a mixture of monoalkylated:bis-alkylated (2:1) adducts. The mixture was dissolved in AcOH (5 ml), iron (112 mg) was added and the reaction was heated to 80° C. for 4 h upon basic preparative HPLC followed by flash column chromatography (×2) (KP-NH, After purification by gradient 0-30% MeOH/DCM and elution with 5-20% MeOH/DCM), the title compound (20 mg, 11%) was obtained as an off-white solid.

1H-NMR (DMSO-d6,500MHz) d[ppm]=12.14(s,1H),8.75(t,J=5.6Hz,1H),8.59(s,1H),8. 41-8.35 (m, 1H), 7.73-7.67 (m, 1H), 7.45 (brs, 2H), 7.43-7.38 (m, 1H), 7.13. −7.07 (m, 2H), 4.64 (dd, J=5.6, 1.3 Hz, 2H), 4.31 (t, J=6.0 Hz, 2H), 2.99 (dt, J=12.3, 6.0 Hz, 4H), 2.94-2.89 (m, 2H)
HPLC MS (Method C): [m/z]: 409.3 [M+H] ^+.
1-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-chloropyridin-2-yl)methyl]-1H-1,2,4- Triazole-3-carboxamide (Example compound No. 170)

In a similar manner using General Procedure 3 at 40° C. for 2 hours, 1H-1,3-benzodiazol-2-carbaldehyde (156 mg, 1.07 mmol), 1-(2- in 2-(40 ml) MeOH. Aminoethyl)-N-[(3-chloropyridin-2-yl)methyl]-1H-1,2,4-triazole-3-carboxamide dihydrochloride (245) (350 mg, 0.89 mmol) and DIPEA (0 0.62 ml, 3.56 mmol) followed by NaBH ₄ (50.5 mg, 1.34 mmol) to give the title compound (190 mg, 52%) as a cream solid after purification by basic preparative HPLC. Was given.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.16 (s, 1H), 8.75 (t, J=5.4 Hz, 1H), 8.66 (s, 1H), 8 .51 (dd, J=4.7, 1.1 Hz, 1H), 7.95 (dd, J=8.1, 1.2 Hz, 1H), 7.49 (br d, J=37.6 Hz, 2H), 7.39 (dd, J=8.0, 4.7 Hz, 1H), 7.12 (s, 2H), 4.67 (d, J=5.4 Hz, 2H), 4.35( t, J=6.0 Hz, 2H), 3.93 (s, 2H), 3.03 (t, J=5.9 Hz, 2H)
HPLCMS (Method C): [m/z]: 411.3 [M+H] ^+.
General scheme 14 above
Methyl 1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1H-pyrazole-4-carboxylate (246)

DIAD (9.39 ml, 43.61 mmol) was added to methyl 1H-pyrazole-4-carboxylate (5 g, 39.65 mmol), tert-butyl(2-hydroxyethyl)carbamate (6.13 ml, 39.65 mmol) and PPh. ₃ (11.44 g, 43.61 mmol) was added dropwise to an ice-cold solution in THF (300 ml). The reaction was then allowed to warm to room temperature and stir for 1.5 hours. The reaction mixture was quenched with water (150 ml) and the layers separated. The aqueous layer was extracted with EtOAc (3 x 150 ml). The combined organic layers were washed with brine, dried (MgSO _4), filtered to give the crude product the solvent was evaporated. Purification by flash column chromatography (eluting with a gradient of 15-100% EtOAc/heptane) gave the title compound (11.3 g, 68%) as a white solid.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=7.93 (s, 1H), 7.87 (s, 1H), 4.25 (t, J=5.3 Hz, 2H), 3. 83 (s, 3H), 3.61 to 3.54 (m, 2H), 1.44 (s, 9H)
HPLCMS (Method A): [m/z]: 270.1 [M+H] ^+.
Ethyl 1-(cyanomethyl)-3,5-dimethyl-1H-pyrazole-4-carboxylate (247)

Ethyl 3,5-dimethyl -1H- pyrazole-4-carboxylate (2g, 11.89mmol), bromoacetonitrile _{(1.24ml, 17.84mmol), K 2} CO 3 (3.29g, 23.78mmol) and acetone The mixture (6 ml) was heated at 100° C. for 1 hour under microwave irradiation. Further bromoacetonitrile (0.828 ml, 11.89 mmol) was added and the mixture was heated under microwave irradiation at 100° C. for another hour. The reaction mixture was concentrated in vacuo and the residue was dissolved in water (100ml) and extracted with EtOAc (5x50ml). Dry the organic extracts combined (MgSO _4), filtered and evaporated in vacuo. Purification by flash column chromatography with elution gradient 0-20% MeOH/DCM gave the title compound (2.22 g, 71%) as an orange solid.

1H-NMR (DMSO-d6, 500MHz): d[ppm]=5.42(s, 2H), 4.21(q, J=7.1Hz, 2H), 2.50(s, 3H), 2 .30 (s, 3H), 1.28 (t, J=7.1Hz, 3H)
HPLC MS (Method A): [m/z]: 207.95 [M+H] ^+.
Ethyl 1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-3,5-dimethyl-1H-pyrazole-4-carboxylate (248)

Ethyl 1-(cyanomethyl)-3,5-dimethyl-1H-pyrazole-4-carboxylate (247) (2.22 g, 9.64 mmol), BOC anhydride (4.21 g, 19.27 mmol), TEA (2 A suspension of .69 ml, 19.27 mmol) and palladium on carbon (10 wt%, 0.103 g, 0.964 mmol) in EtOH (100 ml) was stirred under hydrogen atmosphere for 28 hours. The reaction mixture was filtered and the residue was rinsed with MeOH. The combined filtrate was evaporated in vacuo and the residue was partitioned between water (100ml) and EtOAc (50ml). The phases were separated and the aqueous phase was extracted with EtOAc (3 x 50 ml). The combined organic layers were dried (MgSO _4), filtered and evaporated in vacuo. Purification by flash column chromatography with elution gradient 70-100% EtOAc/heptane gave the title compound (1.52 g, 51%) as a yellow-brown solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=6.90 (s, 1H), 4.18 (q, J=7.1 Hz, 2H), 4.02 (t, J=6. 1 Hz, 2H), 3.21 (q, J=6.1 Hz, 2H), 2.42 (s, 3H), 2.27 (s, 3H), 1.38-1.28 (s, 9H) , 1.26 (t, J=7.1Hz, 3H)
HPLC MS (Method A): [m/z]: 312.45 [M+H] ^+.
Ethyl 1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (248)

Ethyl 3- (trifluoromethyl)-1H-pyrazole-4-carboxylate (3g, 14.41mmol), tert- butyl (2-hydroxyethyl) carbamate (2.45ml, 15.85mmol) and _PPh 3 (4. A solution of 16 g, 15.85 mmol) in THF (50 ml) was stirred at room temperature for 16 hours. Further (2-hydroxyethyl)carbamate (2.45 ml, 15.85 mmol) was added and the reaction was stirred at room temperature for a further 48 hours. The reaction was quenched with water (30 ml) and extracted into EtOAc (3 x 50 ml). The combined organic layers were washed with brine (30ml), dried (MgSO _4), filtered and evaporated to give a yellow oil. Purification by flash column chromatography (eluting with a gradient of 5-80% TBME/heptane) gave a residue which was re-purified by flash column chromatography (eluting with a gradient of 5-60% TBME/heptane). The compound (1.19 g, 21%) was obtained as a white solid.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=7.97 (s, 1H), 4.72 (br s, 1H), 4.32 (q, J=7.1 Hz, 2H), 4 .32-4.27 (m, 2H), 3.59 (app q, J=5.9 Hz, 2H), 1.44 (s, 9H), 1.35 (t, J=7.1 Hz, 3H) )
HPLCMS (Method A): [m/z]: 374 [M+Na] ^+.
1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1H-pyrazole-4-carboxylic acid (249)

In a similar manner to General Procedure 5, LiOH (0.72 g, 30.08 mmol) and 1-(2-{[(tert-butoxy)carbonyl] in THF (80 ml) and water (30 ml) at room temperature for 24 hours. Amino}ethyl)-1H-pyrazole-4-carboxylate (246) (54%, 5g, 10.03mmol) afforded the title compound (2.6g, 96.5%). The compound was used without purification.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.06(s,1H),7.87(s,1H),4.23(t,J=5.8Hz,2H),3 .46 (app q, J=5.5 Hz, 2H), 1.42 (d, J=19.0 Hz, 9H)
HPLC MS (Method A): [m/z]: 255.95 [M+H] ^+.
1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid (250)

In a manner similar to General Procedure 5, at 70° C., ethyl 1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-3,5-dimethyl-in THF (60 ml) and water (30 ml). 1H-pyrazole-4-carboxylate (247) (1 g, 2.58 mmol, 80% purity) and LiOH (0.37 g, 15.49 mmol) gave the title compound (0.417 g, 52%, 90% purity). Obtained as a yellow solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.02 (s, 1H), 6.91 (t, J=5.6 Hz, 1H), 4.00 (t, J=6. 0 Hz, 2H), 3.21 (q, J=6.0 Hz, 2H), 2.40 (s, 3H), 2.26 (s, 3H), 1.37 (s, 9H)
HPLC MS (Method A): [m/z]: 284.05 [M+H] ^+.
1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (251)

In a similar manner to General Procedure 5, LiOH (0.241 g, 10.08 mmol) and ethyl 1-(2-{[(tert-butoxy)carbonyl] in THF/water (25 ml/8 ml) at room temperature for 16 hours. Amino}ethyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (248) (89%, 1.18 g, 2.99 mmol) gave the title compound (0.54 g, 45%) white. Obtained as a solid.

1 H-NMR (CDCl ₃ , 250 MHz): d[ppm]=8.03 (s, 1H), 4.80 (br s, 1H), 4.36-4.18 (br m, 2H), 3. 71-3.54 (m, 2H), 1.45 (s, 9H)
HPLC MS (Method A): [m/z]: 346.1 [M+Na] ^+.
tert-Butyl N-(2-{4-[(pyridin-2-ylmethyl)carbamoyl]-1H-pyrazol-1-yl}ethyl)carbamate (252)

In a similar manner using general procedure 6 1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1H-pyrazole-4-carboxylic acid (249) (0. 50 g, 1.96 mmol), 1-(pyridin-2-yl)methanamine (0.30 ml, 2.94 mmol), DIPEA (1.0 ml, 5.88 mmol) and HATU (1.12 g, 2.94 mmol). After purification by flash column chromatography (eluting with a gradient of 3:2 EtOAc/heptane and 100% EtOAc), the title compound (0.647 g, 56%, 59% pure) was obtained as a yellow oil. The compound was used in the next step without further purification.

_{1H-NMR (CDCl 3, 500MHz} ): d [ppm] = 8.56 (d, J = 4.4Hz, 1H), 7.87 (d, J = 3.8Hz, 2H), 7.68 (td , J=7.7, 1.8 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.24-7.20 (m, 1H), 7.14 (s, 1H). , 4.84 (s, 1H), 4.71 (d, J=4.8 Hz, 2H), 4.25 (t, J=5.4 Hz, 2H), 3.58 (q, J=5. 4Hz, 2H), 1.43 (s, 9H)
HPLC MS (Method A): [m/z]: 346.3 [M+H] ^+.
tert-Butyl N-{2-[4-({5H,6H,7H-cyclopenta[b]pyridin-7-yl}carbamoyl)-1H-pyrazol-1-yl]ethyl}carbamate (253)

In a similar manner using general procedure 6 1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1H-pyrazole-4-carboxylic acid (249) (0. 7 g, 2.74 mmol), 5H,6H,7H-cyclopenta[b]pyridin-7-amine hydrochloride (0.7 g, 4.11 mmol), DIPEA (1.4 ml, 8.23 mmol) and HATU (1.56 g). 4.11 mmol) afforded the title compound (0.709 g, 70%) as an off-white solid after purification by flash chromatography (eluting with a gradient of 80-100% EtOAc/Heptane).

1H-NMR (MeOD-d6,500 MHz): d[ppm]=8.35 (d, J=4.6 Hz, 1H), 8.07 (s, 1H), 7.94 (s, 1H), 7 .73 (d, J=7.8 Hz, 1H), 7.28 (dd, J=7.6, 5.0 Hz, 1H), 5.53 (t, J=8.1 Hz, 1H), 4. 23 (t, J=5.7 Hz, 2H), 3.49-3.43 (m, 2H), 3.13-3.03 (m, 1H), 2.95 (dt, J=16.8). , 8.5 Hz, 1H), 2.66 (ddt, J=11.3, 8.1, 3.9 Hz, 1H), 2.07-1.95 (m, 1H), 1.40 (s, 9H)
HPLCMS (Method A): [m/z]: 372.1 [M+H] ^+.
tert-Butyl N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1H-pyrazol-1-yl)ethyl]carbamate (254)

In a similar manner using general procedure 6 1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1H-pyrazole-4-carboxylic acid (249) (0. 35 g, 1.3 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (0.46 g, 1.95 mmol), DIPEA (1.13 ml, 6.51 mmol) and HATU (0.74 g). , 1.95 mmol) after purification by flash column chromatography (eluting with a gradient of 0-50% MeOH/EtOAc) to afford the title compound (0.4 g, 82%) as an orange foam.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.40-8.37 (m, 1H), 7.89 (s, 2H), 7.46-7.38 (m, 1H), 7.30-7.24 (m, 1H), 4.86 (br s, 1H), 4.78 (dd, J=4.4 and 1.2 Hz, 2H), 4.26 (t, J= 5.3 Hz, 2H), 3.64-3.50 (m, 2H), 1.43 (s, 9H)
HPLCMS (Method A): [m/z]: 364.40 [M+H] ^+.
tert-Butyl N-[2-(4-{[(3-chloropyridin-2-yl)methyl]carbamoyl}-1H-pyrazol-1-yl)ethyl]carbamate (255)

In a similar manner using general procedure 6 at room temperature for 24 hours 1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1H-pyrazole-4-carboxylic acid (in DMF (15 ml)). 249) (0.7 g, 2.74 mmol), (3-chloropyridin-2-yl)methanamine dihydrochloride (0.89 g, 4.11 mmol), DIPEA (2.39 ml, 13.71 mmol) and HATU (1. After purification by flash column chromatography (eluting with a gradient of 0-50% MeOH/EtOAc) by 0.56 g, 4.11 mmol), the title compound (0.79 g, 76%) was obtained as a viscous brown oil. The oil solidified on standing.

_{1H-NMR (CDCl 3, 500MHz} ): d [ppm] = 8.48 (dd, J = 4.7,1.0Hz, 1H), 7.91 (s, 1H), 7.91 (s, 1H ), 7.72 (dd, J=8.0, 1.2 Hz, 1H), 7.50 (br s, 1H), 7.23 (dd, J=8.0, 4.8 Hz, 1H), 4.87 (br s, 1H), 4.78
(D, J=4.2 Hz, 2H), 4.26 (t, J=5.3 Hz, 2H), 3.59 (app q, J=5.6 Hz, 2H), 1.44 (s, 9H). )
HPLCMS (Method A): [m/z]: 380.4 [M+H] ^+.
tert-Butyl N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-3,5-dimethyl-1H-pyrazol-1-yl)ethyl]carbamate (256)

In a manner similar to General Procedure 6 1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-3,5-dimethyl-1H-pyrazole-4 in THF (15 ml) and DMF (3 ml). -Carboxylic acid (250) (0.42 g, 1.33 mmol, purity 90%), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (0.47 g, 2.0 mmol), DIPEA (1 0.16 ml, 6.67 mmol) and HATU (0.76 g, 2.0 mmol) after purification by flash column chromatography (kp-NH, eluting with a gradient of 60-100% EtOAc/heptane) after the title compound (0. 40 g, 77%) was obtained as a colorless glassy solid.

1H-NMR (DMSO-d6,500MHz): d[ppm]=8.38 (d, J=4.7Hz, 1H), 7.81-7.77(m, 1H), 7.71-7. 65 (m, 1H), 7.39 (dt, J=8.6, 4.4 Hz, 1H), 6.94-6.89 (m, 1H), 4.59 (d, J=4.3 Hz) , 2H), 3.99 (t, J=6.5 Hz, 2H), 3.20 (q, J=6.5 Hz, 2H), 2.34 (s, 3H), 2.25 (s, 3H). ), 1.37 (s, 9H)
HPLCMS (Method A): [m/z]: 392.1 [M+H] ^+.
tert-Butyl N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl]carbamate (257)

In a similar manner using general procedure 6 at room temperature for 72 hours 1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-3-(tri) in DMF (3 ml) and THF (15 ml). Fluoromethyl)-1H-pyrazole-4-carboxylic acid (251) (90%, 0.54 g, 1.53 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (0.23 g, After purification by flash column chromatography (eluting with a gradient of 5-100% EtOAc/heptane) by DIPEA (0.87 ml, 5.01 mmol) and HATU (0.57 g, 1.5 mmol). The compound (0.646 g, 65%) was obtained.

_{1H-NMR (CDCl 3, 250MHz} ): d [ppm] = 8.40-8.35 (m, 1H), 7.98 (s, 1H), 7.56 (s, 1H), 7.46- 7.37 (m, 1H), 7.31-7.23 (m, 4H), 4.80 (dd, J=4.3, 1.2Hz, 2H), 4.30 (t, J=5). .4 Hz, 2H), 3.60 (app q, J=6.0 Hz, 2H), 1.44 (s, 9H)
HPLCMS (Method A): [m/z]: 432.1 [M+H] ^+.
1-(2-aminoethyl)-N-(pyridin-2-ylmethyl)-1H-pyrazole-4-carboxamide dihydrochloride (258)

In a similar manner using General Procedure 2 at room temperature for 2.5 hours, 12M HCl (6.5 ml) in MeOH (6.5 ml) and tert-butyl N-(2-{4-[(pyridine-2. -Ylmethyl)carbamoyl]-1H-pyrazol-1-yl}ethyl)carbamate (252) (0.647g, 1.11mmol, 59% purity) gave the title compound (0.513g, quantitative) as a pale yellow oil. Was obtained. The compound was used in the next step without further purification.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=9.16 (s, 1H), 8.77 (s, 1H), 8.33 (s, 1H), 8.13 (s, 2H). ), 8.05 (s, 1H), 7.80 (s, 2H), 4.72 (s, 2H), 4.42 (s, 2H), 3.27 (d, J=5.9Hz, 2H), 3.05-2.78 (m, 3H)
HPLCMS (Method A): [m/z]: 246 [M+H] ^+.
1-(2-aminoethyl)-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl}-1H-pyrazole-4-carboxamide dihydrochloride (259)

In a similar manner using General Procedure 2 at room temperature for 20 hours, 12M HCl (3.2 ml) in MeOH (20 ml) and tert-butyl N-{2-[4-({5H,6H,7H-cyclopenta. [B]Pyridin-7-yl}carbamoyl)-1H-pyrazol-1-yl]ethyl}carbamate (253) (0.709g, 1.909mmol) gave the title compound (0.745g, quantitative) as a gray solid. Was obtained as. ¹ H NMR (500 MHz, Methanol-d4): d[ppm]=8.60 (d, J=5.8 Hz, 1 H), 8.51 (d, J=7.8 Hz, 1 H), 8.29( s, 1H), 8.05 (s, 1H), 7.93 (dd, J=7.7, 6.0 Hz, 1H), 5.80 (t, J=8.4 Hz, 1H), 4. 53-4.49 (m, 2H), 3.46 (t, J=5.7Hz, 2H), 3.39-3.35 (m, 1H), 3.18 (dt, J=17.0). , 8.5 Hz, 1H), 2.83-2.74 (m, 1H), 2.41-2.31 (m, 1H)
HPLCMS (Method A): [m/z]: 272.05 [M+H] ^+.
1-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide dihydrochloride (260)

In a similar manner using General Procedure 2 at room temperature for 16 hours, 12 M HCl (3.67 ml) in MeOH (5 ml) and tert-butyl N-[2-(4-{[(3-fluoropyridine-2. -Yl)Methyl]carbamoyl}-1H-pyrazol-1-yl)ethyl]carbamate (254) (0.4 g, 1.1 mmol) gave the title compound (0.38 g, quantitative) as a cream foam. It was The compound was used in the next step without further purification.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.65 (t, J=5.7 Hz, 1H), 8.38 (dt, J=4.6, 1.4 Hz, 1H), 8.25 (s, 1H), 8.12 (br s, 3H), 8.00-7.97 (m, 1H), 7.73-7.68 (m, 1H), 7.43-7 .39 (m, 1H), 4.59 (dd, J=5.6, 1.5 Hz, 2H), 4.40 (t, J=6.1 Hz, 2H), 3.25 (app h, J =5.7Hz, 2H)
HPLC MS (Method A): [m/z]: 264.05 [M+H] ^+.
1-(2-aminoethyl)-N-[(3-chloropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide dihydrochloride (261)

In a similar manner using General Procedure 2 at room temperature for 25 h, 12 M HCl (6.5 ml) in MeOH (10 ml) and tert-butyl N-[2-(4-{[(3-chloropyridine-2. -Yl)methyl]carbamoyl}-1H-pyrazol-1-yl)ethyl]carbamate (255) (0.79g, 1.97mmol) afforded the title compound (0.7g, 95%) as a beige solid. It was The compound was used in the next step without further purification.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.69 (dd, J=5.5, 1.2Hz, 1H), 8.51 (dd, J=8.3, 1.2Hz) , 1H), 8.26 (s, 1H), 8.05 (s, 1H), 7.86 (dd, J=8.3, 5.5 Hz, 1H), 4.88 (s, 2H), 4.51 (t, J=5.6Hz, 2H), 3.46 (t, J=5.6Hz, 2H)
HPLC MS (Method A): [m/z]: 279.9 [M+H] ^+.
1-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazole-4-carboxamide dihydrochloride (262)

In a manner similar to General Procedure 2, tert-butyl N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-3,5-dimethyl-1H in MeOH (5 ml). -Pyrazol-1-yl)ethyl]carbamate (256) (0.4g, 1.02mmol) and 12M HCl (1.7ml) gave the title compound (0.399g, 93% pure) as a white solid. ..

1H-NMR (Methanol-d4,500MHz): d [ppm] = 8.64 (dd, J = 5.5, 1.2Hz, 1H), 8.33 (t, J = 8.9Hz, 1H), 7.97-7.92 (m, 1H), 4.86-4.85 (m, 2H), 4.34-4.29 (m, 2H), 3.40 (t, J=5.8Hz. , 2H), 2.46 (s, 3H), 2.38 (s, 3H)
HPLCMS (Method A): [m/z]: 292 [M+H] ^+.
1-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide dihydrochloride (263)

In a similar manner using General Procedure 2 at room temperature for 17 hours 12M HCl (2.1 ml) in MeOH (10 ml) and tert-butyl N-[2-(4-{[(3-fluoropyridine-2 -Yl)methyl]carbamoyl}-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl]carbamate (257) (80%, 0.68g, 1.26mmol) with the title compound (0.588g). , 93.4%) was obtained as a pink solid. The compound was used in the next step without further purification.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.80 (t, J=5.7 Hz, 1H), 8.52 (s, 1H), 8.42-8.36 (m, 1H), 8.23 (s, 3H), 7.78-7.68 (m, 1H), 7.48-7.39 (m, 1H), 4.59 (dd, J=5.5). 1.3 Hz, 2 H), 4.50 (t, J=6.0 Hz, 2 H), 3.29 (q, J=5.7 Hz, 2 H), 2.89 (s, 1 H), 2.69 ( s, 7H)
HPLC MS (Method A): [m/z]: 332.2 [M+H] ^+.
1-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-(pyridin-2-ylmethyl)-1H-pyrazole-4-carboxamide (Example Compound No. 92)

In a manner similar to general procedure 3 at room temperature for 65 hours 1-(2-aminoethyl)-N-(pyridin-2-ylmethyl)-1H-pyrazole-4-carboxamide dihydrochloride ((7ml) in MeOH (7ml)). 258) (256 mg, 0.805 mmol), 1H-benzimidazole-2-carbaldehyde (129 mg, 0.885 mmol) and DIPEA (0.70 ml, 4.02 mmol) followed by NaBH ₄ (46 mg, 1.21 mmol). Upon addition, the title compound (58 mg, 19%) was obtained as a pale yellow solid after purification by preparative HPLC.

1H-NMR (DMSO-d6,500MHz): d[ppm]=12.17(s, 1H), 8.68(t, J=6.0Hz, 1H), 8.49(d, J=4. 2 Hz, 1 H), 8.23 (s, 1 H), 7.91 (s, 1 H), 7.74 (td, J=7.7, 1.8 Hz, 1 H), 7.51 (s, 1 H) , 7.45 (s, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.25 (dd, J=7.1, 5.1 Hz, 1H), 7.18-7. 05(m, 2H), 4.49(d, J=6.0Hz, 2H), 4.22(t, J=6.2Hz, 2H), 3.91(s, 2H), 2.97( t, J=6.1 Hz, 2H), 2.45 (s, 1H)
HPLCMS (Method B): [m/z]: 376.2 [M+H] ^+.
1-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl}-1H-pyrazole- 4-carboxamide (Example compound No. 132)

In a similar manner using general procedure 3 at room temperature for 24 hours 1-(2-aminoethyl)-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl} in MeOH (6ml). 1H-pyrazole-4-carboxamide dihydrochloride (259) (150 mg, 0.38 mmol), 1H-benzimidazole-2-carbaldehyde (67 mg, 0.46 mmol) and DIPEA (0.267 ml, 1.53 mmol), After purification by basic preparative HPLC by subsequent addition of NaBH ₄ (22 mg, 0.57 mmol) followed by flash column chromatography (kp-NH, eluting with a gradient of 0-20% MeOH/EtOAc), The title compound (23 mg, 15%) was obtained as a yellow solid.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.35(d, J=4.9Hz, 1H), 8.17(s, 1H), 7.93(s, 1H), 7 .74 (d, J=7.6 Hz, 1H), 7.51 (s, 2H), 7.28 (dd, J=7.6, 4.9 Hz, 1H), 7.20 (dd, J= 6.0, 3.2 Hz, 2H), 5.54 (t, J=8.2 Hz, 1H), 4.29 (t, J=5.9 Hz, 2H), 4.01 (s, 2H), 3.09 (t, J=5.9 Hz, 2H), 3.08-3.04 (m, 1H), 2.99-2.91 (m, 1H), 2.71-2.63 (m , 1H), 2.06-1.97 (m, 1H)
HPLCMS (Method B): [m/z]: 402.1 [M+H] ^+.
1-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide( (Example compound No. 145)

1-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole in MeOH (8 ml) in a similar manner using general procedure 3 for 18 hours at room temperature. 4-carboxamide dihydrochloride (260) (200mg, 0.59mmol) , 1H- benzimidazol-2-carbaldehyde (104 mg, 0.71 mmol) and DIPEA (0.41ml, 2.38mmol), followed by NaBH ₄ After purification by flash column chromatography (kp-NH, elution with a gradient of 0-10% MeOH/DCM) by addition of (32.7 mg, 0.87 mmol), followed by purification by basic preparative HPLC, the title compound. (91 mg, 40%) was obtained as a colorless film.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.15 (brs, 1H), 8.53 (t, J=5.7 Hz, 1H), 8.37 (dt, J=4). .6, 1.4 Hz, 1H), 8.21 (s, 1H), 7.88 (s, 1H), 7.70-7.65 (m, 1H), 7.59-7.41 (m). , 2H), 7.41-7.37 (m, 1H), 7.12 (d, J=4.7Hz, 2H), 4.57 (dd, J=5.7, 1.6Hz, 2H). , 4.21 (t, J=6.2 Hz, 2H), 3.90 (br s, 2H), 2.96 (app br s, 2H)
HPLC MS (Method C): [m/z]: 394.1 [M+H] ^+.
1-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-chloropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide( Example compound No. 138)

In a similar manner to General Procedure 3 1-(2-aminoethyl)-N-[(3-chloropyridin-2-yl)methyl]-1H-pyrazole-4 in MeOH (8 ml) for 16 hours at room temperature. - carboxamide dihydrochloride (261) (200mg, 0.54mmol) , 1H- benzimidazol-2-carbaldehyde (94.5 mg, 0.65 mmol) and DIPEA (0.38ml, 2.16mmol), NaBH 4 and subsequently (30.6 mg, 0.81 mmol) was added to give the title compound (127 mg, 56%) as a pale green foam after purification by basic preparative HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.17 (s, 1H), 8.51-8.46 (m, 2H), 8.23 (s, 1H), 7.92. (Dd, J=8.1, 1.4 Hz, 1H), 7.90 (s, 1H), 7.58-7.41 (br m, 2H), 7.37 (dd, J=8.1). , 4.7 Hz, 1H), 7.17-7.08 (m, 2H), 4.62 (d, J=5.6 Hz, 2H), 4.23 (t, J=6.2 Hz, 2H). , 3.92 (br s, 2H), 2.98 (br s, 2H)
HPLCMS (Method C): [m/z]: 410.2 [M+H] ^+.
1-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-3,5-dimethyl-1H- Pyrazole-4-carboxamide (Example compound No. 142)

In a similar manner using general procedure 3 at room temperature for 16 hours 1-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-3,5 in MeOH (7 ml). -Dimethyl-1H-pyrazole-4-carboxamide dihydrochloride (262) (150 mg, 0.384 mmol), 1H-benzimidazole-2-carbaldehyde (73 mg, 0.499 mmol), DIPEA (0.268 ml, 1.537 mmol). ) And MgSO ₄ (100 mg), followed by NaBH ₄ (22 mg, 0.576 mmol) to give the title compound (14 mg, 9%) as a yellow solid after purification by basic preparative HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.16 (s, 1H), 8.40-8.37 (m, 1H), 7.84 (t, J=5.6 Hz, 1H), 7.72-7.66 (m, 1H), 7.56-7.50 (m, 1H), 7.46-7.42 (m, 1H), 7.40 (dt, J= 8.4, 4.4 Hz, 1H), 7.17-7.09 (m, 2H), 4.59 (d, J=4.3 Hz, 2H), 4.05 (t, J=6.4 Hz). , 2H), 3.92 (s, 2H), 2.90 (t, J=6.4 Hz, 2H), 2.38 (s, 3H), 2.24 (s, 3H).
HPLC MS (Method D): [m/z]: 422.3 [M+H] ^+.
1-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-3-(trifluoromethyl)- 1H-pyrazole-4-carboxamide (Example compound No. 156)

In a similar manner using General Procedure 3 at room temperature for 16 hours 1-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-3-( in MeOH (5 ml). Trifluoromethyl)-1H-pyrazole-4-carboxamide dihydrochloride (263) (81%, 100 mg, 0.20 mmol), 1H-benzimidazole-2-carbaldehyde (35 mg, 0.24 mmol) and DIPEA (0. 14 ml, 0.8 mmol) followed by NaBH ₄ (22 mg, 0.6 mmol) by basic preparative HPLC followed by flash column chromatography (eluting with a gradient of 0-10% MeOH/DCM). After purification, the title compound (12 mg, 13%) was obtained as a white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.15 (s, 1H), 8.69 (t, 1H), 8.45 (s, 1H), 8.37 (d, 1H). ), 7.72-7.66 (m, 1H), 7.53 (d, 1H), 7.45-7.38 (m, 2H), 7.12 (t, 2H), 4.71-. 4.45 (m, 2H), 4.29 (t, 2H), 3.92 (s, 2H), 2.99 (s, 2H)
HPLCMS (Method C): [m/z]: 462.1 [M+H] ^+.
1-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-(pyridin-2-ylmethyl)-1H-pyrazole-4-carboxamide (implementation (Example compound #109)

In a similar manner using general procedure 7 for 6 days at room temperature 1-(2-aminoethyl)-N-(pyridin-2-ylmethyl)-1H-pyrazole-4-carboxamide in DMF (7.5 ml). Preparative by dihydrochloride (258) (250 mg, 0.79 mmol), 2-(2-chloroethyl)-1H-benzimidazole hydrochloride (340 mg, 1.58 mmol) and DIPEA (2.1 ml, 11.8 mmol). HPLC, followed by 4: 6EtOAc / heptane to 100% EtOAc, then 20% MeOH: using 80% DCM (KP-NH) flash column chromatography, followed by preparative HPLC (MeCN / water, _2mM NH 4 _HCO 3) After purification by, the title compound (17 mg, 5%) was obtained as a pale yellow solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.10 (s, 1H), 8.68 (t, J=6.0 Hz, 1H), 8.50 (d, J=4. 1 Hz, 1 H), 8.21 (s, 1 H), 7.90 (s, 1 H), 7.74 (td, J=7.7, 1.8 Hz, 1 H), 7.58-7.33 ( m, 2H), 7.29 (d, J=7.9 Hz, 1H), 7.25 (dd, J=7.4, 4.9 Hz, 1H), 7.09 (dd, J=6.0). , 2.8 Hz, 2H), 4.49 (d, J=6.0 Hz, 2H), 4.19 (t, J=6.2 Hz, 2H), 3.00-2.93 (m, 4H). , 2.91 (t, J=6.2 Hz, 2H), 2.05 (s, 1H)
HPLCMS (Method B): [m/z]: 390.2 [M+H] ^+.
1-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole -4-carboxamide tetrahydrochloride (Example compound No. 111)

In a similar manner using general procedure 7 at 30° C. for 6 days 1-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H- in DMF (15 ml). Pyrazole-4-carboxamide dihydrochloride (260) (0.7 g, 2.08 mmol), 2-(2-chloroethyl)-1H-benzimidazole (0.451 g, 2.499 mmol) and DIPEA (5.4 ml, 31). .23 mmol) gave the product as free base (63 mg) after silica column chromatography (kp-NH, eluting with a gradient of 0-40% MeOH/EtOAc) followed by purification by basic preparative HPLC. It was The free base product was dissolved in MeOH (3 ml) and 12M HCl (2 ml) at room temperature for 2 hours to give the title compound (65 mg, 5.6%) as a brown solid.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.46(s,1H),8.25(s,1H),8.01(s,1H),7.81(dd,J). =6.2, 3.2 Hz, 3H), 7.63 (dd, J=6.2, 3.1 Hz, 3H), 4.78 (s, 2H), 4.64 (s, 2H), 3 .72 (d, J=7.6 Hz, 6H)
HPLCMS (Method B): [m/z]: 408.2 [M+H] ^+.
1-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl} -1H-pyrazole-4-carboxamide trihydrochloride (Example compound No. 131)

In a similar manner using general procedure 7 1-(2-aminoethyl)-N-{5H,6H,7H-cyclopenta[[3H] in DMF (3 ml) heated at room temperature for 72 hours, then 21 hours at 40°C. b] Pyridin-7-yl}-1H-pyrazole-4-carboxamide dihydrochloride (259) (0.2 g, 0.51 mmol), 2-(2-chloroethyl)-1H-benzimidazole hydrochloride (0.13 g) , 0.61 mmol) and DIPEA (0.44 ml, 2.55 mmol) gave the free base product (55 mg) after purified basic preparative HPLC. The free base product was then dissolved in MeOH (3 ml) and 12M HCl (0.5 ml) at room temperature for 2 hours to give the title compound (0.049 g, 18%) as a brown solid.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.60 (d, J=5.2Hz, 1H), 8.51 (d, J=6.8Hz, 1H), 8.31( s, 1H), 8.03 (s, 1H), 7.95-7.91 (m, 1H), 7.83-7.79 (m, 2H), 7.65-7.62 (m, 2H), 5.80(t, J=8.5Hz, 1H), 4.68-4.64(m, 2H), 3.77-3.70(m, 6H), 3.34(d, J=3.3 Hz, 1H), 3.23-3.17 (m, 1H), 2.83-2.75 (m, 1H), 2.39-2.30 (m, 1H).
HPLCMS (Method B): [m/z]: 416.1 [M+H] ^+.
1-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-chloropyridin-2-yl)methyl]-1H-pyrazole -4-carboxamide (Example compound No. 144)

In a similar manner using general procedure 7 1-(2-aminoethyl)-N-[(3-chloropyridine-2-in 2) in DMF (7 ml) heated to 40° C. for 66 hours at room temperature then 90 hours. Iyl)methyl]-1H-pyrazole-4-carboxamide dihydrochloride (261) (0.45 g, 1.28 mmol), 2-(2-chloroethyl)-1H-benzimidazole (0.28 g, 1.53 mmol) and After purification by flash column chromatography (kp-NH, gradient 0-10% MeOH/DCM) by DIPEA (3.3 ml, 19.14 mmol), followed by purification by basic preparative HPLC, the title compound (112 mg, 21%) was obtained as a colorless film.

1H-NMR (DMSO-d6,500MHz): d[ppm]=12.10 (s, 1H), 8.52-8.44 (m, 2H), 8.22 (s, 1H), 7.92. (Dd, J=8.1, 1.4 Hz, 1H), 7.90 (s, 1H), 7.55-7.38 (br m, 2H), 7.37 (dd, J=8.1). , 4.7 Hz, 1H), 7.13-7.07 (m, 2H), 4.63 (d, J=5.7 Hz, 2H), 4.20 (t, J=6.2 Hz, 2H). , 2.99-2.93 (m, 4H), 2.93-2.89 (m, 2H)
HPLCMS (Method C): [m/z]: 424.1 [M+H] ^+.
1-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-3-( Trifluoromethyl)-1H-pyrazole-4-carboxamide (Example compound No. 162)

In a similar manner using General Procedure 8 DBU (62.94 μl, 0.42 mmol) in MeCN (5 ml), room temperature 16 h, 1-(2-aminoethyl)-N-[(3-fluoropyridine- 2-yl)methyl]-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide dihydrochloride (263) (81%, 140 mg, 0.28 mmol) and N-(2-nitrophenyl)propa-2. -Enamide (D) (52.84 mg, 0.27 mmol) gave the residue (0.160 g) as a mixture of monoalkylated:bisalkylated (1:1) adducts.

The residue was dissolved in AcOH (4 ml). Iron (0.03g) was added and the reaction heated to 80°C for 1 hour. The reaction was cooled and diluted with water (5 ml). The mixture was cooled in an ice bath and basified to pH 12 with 10M NaOH. Water (10 ml) was added and the mixture was extracted with CHCl ₃ :IPA (4:1, 4×30 ml). The combined organic layers were dried _(Na 2 _SO 4), filtered and evaporated. Flash column chromatography (gradient 5 to 10% MeOH / DCM, followed by eluting with MeOH / DCM in 0~10% 7N NH _3), Purification by basic prep-HPLC Subsequently, the title compound (19 mg, 13.9 %) was obtained as a colorless oil.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.11 (br s, 1H), 8.69 (t, J=5.6 Hz, 1H), 8.43 (s, 1H), 8.42-8.35 (m, 1H), 7.74-7.65 (m, 1H), 7.52-7.36 (br m, 2H), 7.43-7.37 (m, 1H), 7.15-7.06 (br m, 2H), 4.59-4.55 (m, 2H), 4.26 (t, J=6.1Hz, 2H), 3.02-2. .94 (m, 4H), 2.94-2.89 (m, 2H)
HPLC MS (Method C): [m/z]: 476.2 [M+H] ^+.
Ethyl 1-[2-(benzyloxy)-2-oxoethyl]-1H-pyrazole-4-carboxylate (268)

Benzyl bromoacetate (2.82 ml, 18 mmol) in ethyl 1H- pyrazole-4-carboxylate (2.3 g, 16 mmol) and _{K 2 CO 3 (3.4g, 25mmol} ) in DMF (20 ml) an ice-cold suspension The solution was added dropwise. The mixture was warmed to room temperature and stirred for 2 hours. The mixture was diluted with diethyl ether (100 ml) and washed with water (2 x 40 ml) and brine (5 x 20 ml). The organic phase was dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. Purification by flash chromatography using elution gradient 0-100% DCM/heptane gave the title compound (1.57 g, 33%) as a colorless oil.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.01 (s, 1H), 7.98 (s, 1H), 7.44-7.32 (m, 5H), 5.24( s, 2H), 4.98 (s, 2H), 4.32 (q, J = 7.1Hz, 2H), 1.37 (t, J = 7.1Hz, 3H).
HPLCMS (Method A): [m/z]: 288.95 [M+H] ^+.
2-[4-(ethoxycarbonyl)-1H-pyrazol-1-yl]acetic acid (269)

Ethyl 1-[2-(benzyloxy)-2-oxoethyl]-1H-pyrazole-4-carboxylate (268) (1.57 g, 5.44 mmol) and palladium on carbon (10 wt%, 0.590 g, 0. A suspension of 55 mol) in EtOH (50 ml) was stirred under a hydrogen atmosphere for 2.5 hours. The mixture was filtered through a Celite plug and the residue rinsed with MeOH. The combined filtrate was evaporated in vacuo to give the title compound (0.99 mg, 92%) as a yellow solid.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.07 (s, 1H), 8.03 (s, 1H), 5.07 (s, 2H), 4.34 (q, J= 7.1Hz, 2H), 1.37(t, J=7.1Hz, 3H)
HPLCMS (Method A): [m/z]: 198.9 [M+H] ^+.
Ethyl 1-({[2-(1H-1,3-benzodiazol-2-yl)ethyl]carbamoyl}methyl)-1H-pyrazole-4-carboxylate (270)

In a manner similar to general procedure 6 HATU (1.1 g, 2.88 mmol), 2-[4-(ethoxycarbonyl)-1H-pyrazol-1-yl]acetic acid in THF (30 ml) for 2 hours at room temperature. (269) (0.476 g, 2.4 mmol), 2-(1H-1,3-benzodiazol-2-yl)ethane-1-amine dihydrochloride (0.62 g, 2.64 mmol) and DIPEA ( After purification by flash chromatography (gradient elution 0-8% MeOH/DCM) by 1.67 ml, 9.61 mmol, the title compound (0.676 g, 82%) was obtained as a white solid.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.01 (s, 1H), 7.87 (s, 1H), 7.62 (m, 2H), 7.36 (m, 3H). , 4.90 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.80 (q, J=5.9 Hz, 3H), 3.39 (t, J=5. 9Hz, 2H), 1.34 (t, J=7.1Hz, 3H)
HPLCMS (Method A): [m/z]: 342.1 [M+H] ^+.
1-({[2-(1H-1,3-benzodiazol-2-yl)ethyl]carbamoyl}methyl)-1H-pyrazole-4-carboxylic acid (271)

In a manner similar to General Procedure 5, ethyl 1-({[2-(1H-1,3-benzodiazol-2-yl)ethyl]carbamoyl in THF/water (30 ml/4 ml) at room temperature for 16 hours. } Methyl)-1H-pyrazole-4-carboxylate (270) (667 mg, 1.95 mmol) and LiOH (140 mg, 5.85 mmol) gave the crude title compound (420 mg) as a white residue.

HPLCMS (Method A): [m/z]: 314 [M+H] ^+.
1-({[2-(1H-1,3-benzodiazol-2-yl)ethyl]carbamoyl}methyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4 -Carboxamide dihydrochloride (Example compound No. 117)

In a manner similar to General Procedure 6 crude 1-({[2-(1H-1,3-benzodiazol-2-yl)ethyl]carbamoyl}methyl)- in THF (10 ml) and DMF (2 ml). 1H-pyrazole-4-carboxylic acid (271) (200 mg), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (140 mg, 0.7 mmol), DIPEA (0.44 ml, 2.55 mmol). And HATU (290 mg, 0.76 mmol) after flash column chromatography (eluting with a gradient of 0-20% MeOH/DCM) followed by purification by basic preparative HPLC afforded the title compound as the free base. The free base was converted to the dihydrochloride salt (28 mg, 9%) after treatment with 12M HCl (1 ml) in MeOH (5 ml).

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.49(d, J=5.2Hz, 1H), 8.13(s, 1H), 8.00-7.92(m, 2H), 7.76 (dt, J=6.7, 3.4 Hz, 2H), 7.67 (dt, J=8.8, 4.8 Hz, 1H), 7.59 (dt, J=6) .2, 3.4 Hz, 2H), 4.88 (s, 2H), 4.79 (d, J=1.4 Hz, 2H), 3.77 (t, J=6.4 Hz, 2H), 3 .39 (t, J=6.4 Hz, 2H)
HPLC MS (Method C): [m/z]: 422.2 [M+H] ^+.
General Scheme 15 above:
1-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}-1H-pyrazole-4-carboxylic acid (272)

Ethyl 1H-pyrazole-4-carboxylate (0.2 g, 1.427 mmol), tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (0.362 g, 1.296 mmol) in DMF (5 ml). ) Was stirred for 5 minutes. The reaction was cooled to 0° C. and NaH (0.234 g, 5.85 mmol) was added in small portions. Once gas evolution ceased, the reaction was heated to 50° C. for 26 hours. The reaction was cooled, quenched with water (15 ml) and evaporated to dryness. Water (40 ml) was added and the aqueous layer was extracted with EtOAc (3 x 15 ml). The aqueous layer was acidified to pH 3 with saturated KHSO ₄ and extracted with EtOAc (4×20 ml). The combined organic layers were dried (MgSO _4), filtered, and evaporated to give the title compound (0.331 g, 79%) as a pale yellow solid.

1H-NMR (DMSO-d6,500MHz): d[ppm]=8.29 (s, 1H), 7.81 (s, 1H), 4.44-4.36 (m, 1H), 4.08. -3.97 (m, 2H), 2.89 (s, 2H), 2.01-1.95 (m, 2H), 1.79 (qd, J = 12.4, 4.4Hz, 2H) , 1.41 (s, 9H)
HPLC MS (Method A): [m/z]: 318.0 [M+Na] ^+.
tert-Butyl 4-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1H-pyrazol-1-yl)piperidine-1-carboxylate (273)

In a similar manner using General Procedure 6 1-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}-1H-pyrazole-4-carboxylic acid in THF (15 ml) and DMF (3 ml). (272) (301 mg, 1.02 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (358 mg, 1.53 mmol), DIPEA (0.8 ml), HATU (581 mg, 1.53 mmol) ), after purification by flash column chromatography (eluting with a gradient of 20-100% EtOAc/heptane) to give the title compound (315 mg, 65%) as a glassy solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.51 (t, J=5.7 Hz, 1H), 8.37 (dt, J=4.6 and 1.5 Hz, 1H), 8.25 (s, 1H), 7.89 (s, 1H), 7.71-7.64 (m, 1H), 7.42-7.36 (m, 1H), 4.57 (dd, J=5.7, 1.5 Hz, 2H), 4.44-4.32 (m, 1H), 4.04-3.96 (m, 2H), 2.89 (br s, 2H), 2 .01 (s, 2H), 1.74 (qd, J=12.4, 4.4 Hz, 2H), 1.41 (s, 9H)
HPLCMS (Method A): [m/z]: 404.1 [M+H] ^+.
N-[(3-fluoropyridin-2-yl)methyl]-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide dihydrochloride (274)

In a similar manner using General Procedure 2 at 35° C. for 16 h, 12 M HCl (1.1 ml) in MeOH (4 ml) and tert-butyl 4-(4-{[(3-fluoropyridin-2-yl). ) Methyl]carbamoyl}-1H-pyrazol-1-yl)piperidine-1-carboxylate (273) (315 mg, 0.664 mmol) gave the title compound (277 mg) as an off-white solid. The compound was used in the next step without further purification.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.54-8.47 (m, 1H), 8.22 (d, J=2.4Hz, 1H), 8.00-8. 11 (m, 1H), 7.98 (s, 1H), 7.69-7.78 (m, 1H), 4.80 (s, 2H), 4.66-4.56 (m, 1H) , 3.56 (dt, J=13.1, 3.4 Hz, 2H), 3.22 (td, J=12.8, 3.4 Hz, 2H), 2.38-2.19 (m, 4H). )
HPLCMS (Method A): [m/z]: 304 [M+H] ^+.
1-[1-(1H-1,3-benzodiazol-2-ylmethyl)piperidin-4-yl]-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide (Example compound No. 150)

In a manner similar to general procedure 7, 2-(chloromethyl)-1H-benzimidazole (71 mg, 0.424 mmol), N-[(3-fluoropyridine-2) in DMF (2 ml) for 16 hours at 30° C. -Yl)methyl]-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide (274) (99 mg, 0.326 mmol) and DIPEA (0.171 ml, 0.98 mmol) for basic preparative. After purification by HPLC followed by further purification by flash column chromatography (kp-NH, eluting with a gradient of 0-20% MeOH/EtOAc), the title compound (21 mg, 15%) was obtained as a white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.28 (s, 1H), 8.52 (t, J=5.7 Hz, 1H), 8.37 (dt, J=4. 6,1.5 Hz, 1H), 8.22 (s, 1H), 7.89 (s, 1H), 7.71-7.65 (m, 1H), 7.54 (br s, 1H), 7.44 (br s, 1H), 7.42-7.36 (m, 1H), 7.14 (br s, 2H), 4.58 (dd, J=5.7, 1.6Hz, 2H ), 4.26-4.12 (m, 1H), 3.77 (s, 2H), 2.95 (d, J=12.0Hz, 2H), 2.32-2.23 (m, 2H). ), 2.05-1.94 (m, 4H)
HPLC MS (Method D): [m/z]: 434.3 [M+H] ^+.
1-{1-[2-(1H-1,3-benzodiazol-2-yl)ethyl]piperidin-4-yl}-N-[(3-fluoropyridin-2-yl)methyl]-1H- Pyrazole-4-carboxamide (Example compound 198)

In a similar manner to General Procedure 8 for 17 hours at room temperature DBU (0.28 ml, 1.89 mmol) in MeCN (10 ml), N-[(3-fluoropyridin-2-yl)methyl]-1-( Piperidin-4-yl)-1H-pyrazole-4-carboxamide dihydrochloride (274) (248 mg, 0.47 mmol) and N-(2-nitrophenyl)prop-2-enamide (D) (154 mg, 0.8 mmol). ) Gave the required intermediate (200 mg, 82%) and after purification by flash column chromatography (eluting with a gradient of 0-25% MeOH/EtOAc) the title compound was obtained as a yellow solid.

HPLC MS (Method A): [m/z]: 496.1 [M+H] ^+.
Treatment of the intermediate with iron powder (87 mg, 1.56 mmol) in AcOH (3 ml) for a further 1.5 h at 80° C. after purification by flash column chromatography eluting with 0-20% MeOH/DCM, the title compound was obtained. (72 mg, 33%) was obtained as an off-white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.14 (s, 1H), 8.51 (t, J=5.7 Hz, 1H), 8.38 (dt, J=4. 6,1.5 Hz, 1H), 8.24 (s, 1H), 7.89 (s, 1H), 7.72-7.65 (m, 1H), 7.51 (s, 1H), 7 .46-7.37 (m, 2H), 7.11 (d, J=5.1Hz, 2H), 4.58 (dd, J=5.7, 1.6Hz, 2H), 4.22- 4.12 (m, 1H), 3.07-2.96 (m, 4H), 2.82 (t, J=7.5Hz, 2H), 2.23-2.14 (m, 2H), 2.05-1.97 (m, 2H), 1.95-1.86 (m, 2H)
HPLC MS (Method C): [m/z]: 448.3 [M+H] ^+.
tert-Butyl 3-{[4-(ethoxycarbonyl)-1H-pyrazol-1-yl]methyl}piperidine-1-carboxylate (275)

Ethyl 1H-pyrazole-4-carboxylate (334 mg, 2.38 mmol), tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (667 mg, 3.1 mmol) and triphenylphosphine (1.25 g, 4. 8 mmol) was dissolved in THF (30 ml) and cooled in an ice water bath. DIAD (0.94 ml, 4.8 mmol) was added dropwise. The mixture was stirred for 18 hours while warming to room temperature. The reaction mixture was diluted with ethyl acetate (80 ml) and washed with saturated NaHCO ₃ (aq) (50 ml) and brine (50 ml). The organic phase was dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. Purification by flash chromatography using a gradient elution of 0-40% EtOAc/heptane gave the crude title compound (2.23 g) as a colorless oil. The crude product was used in the next step without further purification.

HPLC MS (Method A): [m/z]: 338.15 [M+H] ^+.
1-({1-[(tert-butoxy)carbonyl]piperidin-3-yl}methyl)-1H-pyrazole-4-carboxylic acid (276)

In a similar manner using general procedure 5, tert-butyl 3-{[4-(ethoxycarbonyl)-1H-pyrazol-1-yl]methyl}piperidine-1-carboxy in THF/water (20 ml/20 ml). The rate (275) (2.23 g, 4.69 mmol, 71% purity) and LiOH (1.12 g, 0.05 mol) gave the crude product (638 mg, 16%, 38% purity) as a colorless oil. ..

HPLCMS (Method A): [m/z]: 310.05 [M+H] ^+.
tert-Butyl 3-[(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1H-pyrazol-1-yl)methyl]piperidine-1-carboxylate (277)

In a similar manner using general procedure 6 1-({1-[(tert-butoxy)carbonyl]piperidin-3-yl}methyl)-1H-pyrazole-4 in THF (40 ml) and DMF (5 ml). -Carboxylic acid (276) (0.638 g, 2.06 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (0.451 g, 2.27 mmol), DIPEA (1.26 ml, 7) .2 mmol) and HATU (1.18 g, 3.1 mmol) followed by purification by flash column chromatography (eluting with 0-100% EtOAc/heptane, followed by a gradient of 4-8% MeOH/EtOAc). (0.348 g, 32%, purity 79%) was obtained as a hygroscopic yellow solid.

HPLCMS (Method A): [m/z]: 418.15 [M+H] ^+.
N-[(3-fluoropyridin-2-yl)methyl]-1-(piperidin-3-ylmethyl)-1H-pyrazole-4-carboxamide (278)

In a similar manner using General Procedure 2, tert-butyl 3-[(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1H-pyrazol-1-yl)methyl]piperidine- After purification with 1-carboxylate (277) (348 mg, 0.83 mmol) and 12M HCl (0.69 ml) using a SCX-2 cartridge, rinsing with DCM and MeOH, then eluting with 7N ammonia in MeOH. The title compound (182 mg, 64%) was obtained as the free base.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.36 (dt, J=4.7, 1.1Hz, 1H), 8.18(s, 1H), 7.97(s, 1H), 7.60 (ddd, J=9.8, 8.4, 1.2 Hz, 1H), 7.39 (dt, J=8.6, 4.4 Hz, 1H), 4.73 (d , J=1.5 Hz, 2H), 4.18 (td, J=7.1, 2.6 Hz, 2H), 3.29-3.22 (m, 1H), 3.19-3.13( m, 1H), 2.81 (td, J=12.5, 3.1Hz, 1H), 2.70 (t, J=12.1Hz, 1H), 2.42-2.30 (m, 1H) ), 1.94-1.85 (m, 1H), 1.83-1.66 (m, 2H), 1.35-1.22 (m, 1H).
HPLC MS (Method A): [m/z]: 318.10 [M+H] ^+.
1-{[1-(1H-1,3-benzodiazol-2-ylmethyl)piperidin-3-yl]methyl}-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole- 4-carboxamide (Example compound No. 153)

In a similar manner using general procedure 7 N-[(3-fluoropyridin-2-yl)methyl]-1-(piperidin-3-ylmethyl)-1H-pyrazole-4-carboxamide in DMF (8 ml). Basic preparative HPLC with (278) (180 mg, 0.57 mmol), 2-(chloromethyl)-1H-1,3-benzodiazole (189 mg, 1.13 mmol) and DIPEA (180 mg, 1.4 mmol). After purification by, the title compound (66 mg, 25%) was obtained.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.20 (s, 1H), 8.54 (t, J=5.7 Hz, 1H), 8.37 (dt, J=4. 6,1.2 Hz, 1H), 8.16 (s, 1H), 7.88 (s, 1H), 7.71-7.65 (m, 1H), 7.53 (d, J=7. 4 Hz, 1H), 7.45-7.36 (m, 2H), 7.18-7.07 (m, 2H), 5.75 (s, 0H), 4.60-4.54 (m, 2H), 4.12-3.99 (m, 2H), 3.67 (q, J = 14.0 Hz, 2H), 2.71-2.62 (m, 3H), 2.17-2. 04 (m, 2H), 1.96 (t, J = 10.4Hz, 1H), 1.67-1.58 (m, 1H), 1.54-1.38 (m, 2H), 1. 05-0.91 (m, 1H)
HPLC MS (Method C): [m/z]: 448.3 [M+H] ^+.
Ethyl 1-({1-[(tert-butoxy)carbonyl]azetidin-3-yl}methyl)-1H-pyrazole-4-carboxylate (279)

Ethyl 1H-pyrazole-4-carboxylate (0.55 g, 3.92 mmol), tert-butyl 3-(bromomethyl)azetidine-1-carboxylate (0.982 g, 3.92 mmol) and potassium carbonate in DMF (10 ml). (1.08 g, 8 mmol) was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with EtOAc (3 x 50 ml). The combined organic extracts were washed with brine (4×50 ml), dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo to give the title compound (1.33 g) as a pale yellow oil. It was

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=7.92 (s, 1H), 7.90 (s, 1H), 4.38-4.26 (m, 4H), 4.06( t, J=9.0 Hz, 2H), 3.74 (dd, J=9.0, 5.1 Hz, 2H), 3.17-3.01 (m, 1H), 1.46 (s, 9H). ), 1.37 (t, J=7.1 Hz, 3H)
HPLCMS (Method A): [m/z]: 310.15 [M+H] ^+.
1-({1-[(tert-butoxy)carbonyl]azetidin-3-yl}methyl)-1H-pyrazole-4-carboxylic acid (280)

In a similar manner using general procedure 5 LiOH (2.06 g, 86 mmol) and ethyl 1-({1-[(tert-butoxy)carbonyl]azetidine-3-in THF (30 ml) and water (30 ml). Il}methyl)-1H-pyrazole-4-carboxylate (279) (1.33 g, 4.3 mmol) afforded the title compound (1.02 g, 83%) as a white solid.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=12.31 (s, 1H), 8.31 (s, 1H), 7.81 (s, 1H), 4.36 (d, J= 7.3 Hz, 2H), 3.94-3.81 (m, 2H), 3.72-3.61 (m, 2H), 3.07-2.89 (m, 1H), 1.37( s, 9H)
HPLC MS (Method A): [m/z]: 304.05 [M+Na] ^+.
tert-Butyl 3-[(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1H-pyrazol-1-yl)methyl]azetidine-1-carboxylate (281)

In a similar manner using general procedure 6 1-({1-[(tert-butoxy)carbonyl]azetidin-3-yl}methyl)-1H-pyrazole-4-carboxylic acid (280 in DCM (30 ml). ) (500 mg, 1.78 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (389 mg, 1.96 mmol), DIPEA (1.1 ml, 6 mmol) and HATU (740 mg, 2 mmol). After purification by flash column chromatography using a gradient elution of 50-100% EtOAc/heptane followed by 0-10% MeOH/EtOAc, the title compound (624 mg, 89%) was obtained as a colorless oil.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.32 (dt, J=4.7, 1.1 Hz, 1H), 7.84 (s, 1H), 7.79 (s, 1H). ), 7.35 (m, 1H), 7.24-7.20 (m, 1H), 4.71 (dd, J=4.5, 1.3 Hz, 2H), 4.27 (d, J). =7.6 Hz, 2H), 3.97 (t, J=8.6 Hz, 2H), 3.66 (dt, J=7.6, 3.9 Hz, 2H), 3.02-2.98 ( m, 1H), 1.36 (s, 9H)
HPLCMS (Method A): [m/z]: 390.1 [M+H] ^+.
1-(azetidin-3-ylmethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide (282)

In a similar manner using general procedure 2 tert-butyl 3-[(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1H-pyrazol-1-yl in MeOH (20 ml). ) Methyl]azetidine-1-carboxylate (281) (624 mg, 1.6 mmol) and 12M HCl (2 ml), purified with SCX-2 cartridge, rinsed with DCM and MeOH, then with 7N ammonia in MeOH. After elution, the title compound (248 mg, 54%) was obtained as a white solid.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.42 (d, J=4.6 Hz, 1H), 7.94 (s, 1H), 7.88 (s, 1H), 7. 44 (t, J=9.3 Hz, 1H), 7.34-7.25 (m, 1H), 4.81 (d, J=4.2 Hz, 2H), 4.42 (d, J=7) .4 Hz, 2H), 3.82 (t, J=8.2 Hz, 2H), 3.55-3.47 (m, 2H), 3.28 (m, 1H)
HPLCMS (Method A): [m/z]: 290 [M+H] ^+.
1-{[1-(1H-1,3-benzodiazol-2-ylmethyl)azetidin-3-yl]methyl}-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole- 4-carboxamide (Example compound 187)

In a similar manner using general procedure 3 at room temperature for 18 hours 1-(azetidin-3-ylmethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H- in MeOH (5 ml). Pyrazole-4-carboxamide (281) (50 mg, 0.17 mmol), 1H-benzimidazole-2-carbaldehyde (37.9 mg, 0.26 mmol), DIPEA (0.06 ml, 0.34 mmol) and MgSO ₄ (300 mg). ), followed by the addition of NaBH ₄ (7 mg, 0.17 mmol) to give the title compound (32 mg, 43%) as a pale yellow solid after purification by basic preparative HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.08 (s, 1H), 8.54 (t, J=5.7 Hz, 1H), 8.37 (dt, J=4. 6,1.4 Hz, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 7.68 (ddd, J=10.1, 8.3, 1.3 Hz, 1H), 7.47 (s, 2H), 7.40 (dt, J=8.6, 4.4 Hz, 1H), 7.15-7.10 (m, 2H), 4.57 (dd, J=5) .6, 1.5 Hz, 2H), 4.35 (d, J=7.5 Hz, 2H), 3.77 (s, 2H), 3.38 (t, J=7.5 Hz, 2H), 3 .12-3.05 (m, 2H), 2.89-2.79 (m, 1H)
HPLCMS (Method C): [m/z]: 420.1 [M+H] ^+.
1-({1-[2-(1H-1,3-benzodiazol-2-yl)ethyl]azetidin-3-yl}methyl)-N-[(3-fluoropyridin-2-yl)methyl] -1H-pyrazole-4-carboxamide [Example compound No. 192]

In a similar manner using general procedure 8 1-(azetidin-3-ylmethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide in MeCN (10 ml). Crude intermediate with (281) (200 mg, 0.69 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (139.5 mg, 0.73 mmol) and DBU (0.12 ml, 0.83 mmol). A body was obtained which was further reacted with iron powder (130 mg) in AcOH (3 ml). Purification by basic preparative HPLC followed by flash column chromatography (eluting with a gradient of 0-20% MeOH/DCM) afforded the title compound (67 mg, 25%) as a white solid.

1H-NMR (Methanol-d4,500 MHz): d[ppm]=8.36 (dt, J=4.5, 1.3 Hz, 1H), 8.12 (s, 1H), 7.93 (s, 1H), 7.61 (ddd, J=9.8, 8.5, 1.3 Hz, 1H), 7.52 (td, J=6.1, 3.1 Hz, 2H), 7.40 (dt , J=8.5, 4.5 Hz, 1H), 7.24-7.17 (m, 2H), 4.73 (d, J=1.6 Hz, 2H), 4.37 (d, J= 7.2 Hz, 2 H), 3.45 (t, J=7.9 Hz, 2 H), 3.14-3.07 (m, 2 H), 3.00 (dq, J=13.8, 7.0 Hz) , 1H), 2.94 (s, 4H)
HPLC MS (Method C): [m/z]: 434.2 [M+H] ^+.
General scheme 16 above
Methyl 1H-pyrazole-4-carboxylate (282)

1H-Pyrazole-4-carboxylic acid (20 g, 178.4 mmol) and sulfuric acid (39.65 ml) in MeOH (200 ml) were heated at 70° C. for 20 hours. The reaction was cooled to room temperature and concentrated in vacuo. The pH was adjusted to about 6 by adding aqueous NaOH solution. The aqueous layer was extracted with EtOAc (3 × 200ml), dried the combined organic extracts (MgSO _4), filtered, and evaporated in vacuo to give the title compound (18.5 g, 78%) as a white solid Was obtained.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.10 (s, 2H), 3.87 (s, 3H)
HPLC MS (Method A): [m/z]: 126.85 [M+H] ^+.
Methyl 1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazole-4-carboxylate (283)

Methyl 1H-pyrazole-4-carboxylate (282) (3.34 g, 26.48 mmol), 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (10.93 g, 34.43 mmol) and potassium carbonate (10. A suspension of 98 g, 79 mmol) in DMF (70 ml) was heated at 100° C. for 3 hours. The reaction mixture was cooled to room temperature and diluted with water (150 ml). The mixture was extracted with EtOAc (3 x 150 ml), the combined organic extracts were washed with brine (5 x 100 ml), dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. The residue was run through a silica plug (approx. 15 g) (eluted with 10-20% EtOAc/heptane) and the eluent was evaporated in vacuo to give the title compound (4.03 g, 44%) after precipitation from EtOAc/heptane. Obtained as a white solid.

1H-NMR (CDCl ₃ , 250 MHz): d[ppm]=8.14 (s, 1H), 7.96 (s, 1H), 7.49-7.42 (m, 4H), 7.36-. 7.17 (m, 6H), 4.98 (m, 1H), 4.54 (s, 1H), 3.86 (s, 3H), 3.75-3.69 (td, J=7. 2,1.5Hz, 2H), 3.54-3.45 (m, 2H)
HPLC MS (Method A): [m/z]: 348.10 [M+H] ^+.
1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazole-4-carboxylic acid (284)

In a manner similar to General Procedure 5, methyl 1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazole-4-carboxylate (283) (2.3) in THF/water (20 ml/20 ml). 1 g, 6.04 mmol) and LiOH (1.45 g, 60 mmol) gave the title compound (1.95 g, 93%) as a white solid.

1H-NMR (CDCl ₃ , 250 MHz): d[ppm]=8.15 (s, 1H), 8.04 (s, 1H), 7.82-7.70 (m, 4H), 7.51- 7.37 (m, 6H), 5.65-5.55 (m, 1H), 5.55-5.42 (m, 1H), 4.84-4.69 (m, 2H), 4. 39-4.25 (m, 2H)
HPLCMS (Method A): [m/z]: 334.1 [M+H] ^+.
1-[1-(diphenylmethyl)azetidin-3-yl]-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide (285)

In a manner similar to general procedure 6 1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazole-4-carboxylic acid (284) (1..) in THF (50 ml) and DMF (10 ml). 18 g, 2.46 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (0.587 g, 2.95 mmol), DIPEA (1.71 ml, 9.82 mmol) and HATU (1.21 g). 3.19 mmol) afforded the title compound (1.06 g, 82%) as a yellow solid after purification by flash column chromatography (eluting with a gradient of 60-100% EtOAc/heptane).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.59 (t, J=5.7 Hz, 1H), 8.40 (s, 1H), 8.37 (d, J=4. 6 Hz, 1 H), 7.93 (s, 1 H), 7.68 (t, J=9.3 Hz, 1 H), 7.47 (m, 4 H), 7.39 (m, 1 H), 7.29. (T, J=7.6 Hz, 4H), 7.19 (t, J=7.3 Hz, 2H), 5.04 (p, J=6.8 Hz, 1H), 4.62-4.56( m, 3H), 3.59 (t, J=7.7 Hz, 2H), 3.35 (s, 2H)
HPLCMS (Method A): [m/z]: 442.15 [M+H] ^+.
N-{5H,6H,7H-Cyclopenta[b]pyridin-7-yl}-1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazole-4-carboxamide (286)

In a similar manner to General Procedure 6 1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazole-4-carboxylic acid (284) (500 mg, 1.5 mmol) in DCM (20 ml), Crude title compound (949 mg) by 5H,6H,7H-cyclopenta[b]pyridin-7-amine dihydrochloride (404 mg, 1.95 mmol), DIPEA (0.86 ml, 5 mmol) and HATU (0.74 g, 2 mmol). Was obtained as a white residue which was used in the next step without further purification.

HPLCMS (Method A): [m/z]: 450.15 [M+H] ^+.
1-(azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide (287)

1-[1-(diphenylmethyl)azetidin-3-yl]-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide (285) (1.06 g, 2.01 mmol) ) And Pd/C (10%) (0.20 g, 0.201 mmol) were suspended in EtOH (11 ml). A solution of TEA (0.849 ml, 6.04 mmol) and formic acid (0.228 ml, 6.04 mmol) in EtOH (11 ml) was added and the reaction mixture was stirred under reflux for 2 hours. The mixture was cooled to room temperature, filtered through a Celite plug and the residue was rinsed with MeOH (10 ml). The filtrate was evaporated in vacuo to give crude material. Purify using SCX-2 cartridge, wash with DCM and MeOH and elute with 7N ammonia/MeOH to give the title compound (0.354 g, 56%) as a colorless oil.

1H-NMR (DMSO-d6, 500MHz): d[ppm]=8.57(t, J=5.6Hz, 1H), 8.37(d, J=4.6Hz, 1H), 8.34( s, 1H), 7.93 (s, 1H), 7.72-7.65 (m, 1H), 7.40 (dd, J=8.5, 4.3 Hz, 1H), 5.18 ( p, J=7.3 Hz, 1H), 4.58 (dd, J=5.6, 1.4 Hz, 2H), 3.84 (t, J=7.7 Hz, 2H), 3.73 (t , J=8.1Hz, 2H)
HPLCMS (Method A): [m/z]: 276.1 [M+H] ^+.
1-(azetidin-3-yl)-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl}-1H-pyrazole-4-carboxamide (288)

Crude N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl}-1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazole-4-carboxamide (286) (949 mg). And palladium (10 wt% on carbon, 0.12 g, 0.11 mmol) were suspended in EtOH (20 ml). TEA (454 μL, 3 mmol) and formic acid (125 μL, 3 mmol) in EtOH (20 ml) were added and the mixture was heated under reflux for 1 hour. The reaction mixture was cooled to room temperature and filtered through a Celite plug. The residue was rinsed with MeOH and the combined filtrate was evaporated in vacuo. The residue was dissolved in a minimum amount of MeOH, purified by passing through a SCX-2 cartridge, rinsed with DCM and MeOH and eluted with 7N ammonia in MeOH. Evaporation of the basic eluent gave the title compound (342 mg, quantitative) as a white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.40-8.34 (m, 3H), 7.94 (s, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.22 (dd, J=7.6, 4.9 Hz, 1H), 5.48-5.40 (m, 1H), 5.18 (m, 1H), 3.88-3. 81 (m, 2H), 3.78-3.71 (m, 2H), 2.98 (ddd, J = 16.0, 8.9, 3.0Hz, 1H), 2.86 (dt, J). =16.0, 8.3 Hz, 2H), 2.47 (dd, J=6.5, 4.8 Hz, 1H), 1.95-1.84 (m, 1H)
HPLC MS (Method A): [m/z]: 284.05 [M+H] ^+.
1-[1-(1H-1,3-benzodiazol-2-ylmethyl)azetidin-3-yl]-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide [Example Compound No. 136]

In a similar manner using General Procedure 3 at room temperature for 3 days 1-(azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1H- in MeOH (8 ml). Pyrazole-4-carboxamide (287) (196 mg, 0.71 mmol), 1H-1,3-benzodiazol-2-carbaldehyde (125 mg, 0.85 mmol) and MgSO ₄ (100 mg) followed by NaBH ₄ (81 mg). , 2.1 mmol) was added to give the title compound (82 mg, 28%) as a white solid after purification by basic preparative HPLC.

1H-NMR (DMSO-d6,500MHz): d[ppm]=12.32(s, 1H), 8.58(t, J=5.7Hz, 1H), 8.43(s, 1H), 8 .39-8.37 (m, 1H), 7.96 (s, 1H), 7.69 (ddd, J=10.0, 8.3, 1.2Hz, 1H), 7.61-7. 45 (m, 2H), 7.40 (dt, J=8.6, 4.4 Hz, 1H), 7.17-7.10 (m, 2H), 5.06 (m, 1H), 4. 59 (dd, J=5.7, 1.5 Hz, 2H), 3.92 (s, 2H), 3.85-3.81 (m, 2H), 3.61-3.57 (m, 2H). )
HPLC MS (Method C): [m/z]: 406.2 [M+H] ^+.
1-{1-[2-(1H-1,3-benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-[(3-fluoropyridin-2-yl)methyl]-1H- Pyrazole-4-carboxamide (Example compound No. 167)

In a manner similar to general procedure 8 1-(azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide (287) in MeCN (12 ml). ) (364 mg, 1.32 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (254 mg, 1.32 mmol) and DBU (0.197 ml, 1.32 mmol) to give the crude intermediate. This was treated with AcOH (8 ml) and iron powder (62 mg) to give the title compound (104 mg, 43%) as a white solid after purification by basic preparative HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.15 (s, 1H), 8.56 (t, J=5.7 Hz, 1H), 8.37 (d, J=4. 6 Hz, 1 H), 8.34 (s, 1 H), 7.93 (s, 1 H), 7.71-7.65 (m, 1 H), 7.49 (br s, 1 H), 7.45- 7.37 (m, 2H), 7.14-7.07 (m, 2H), 4.98 (p, J=6.8Hz, 1H), 4.59-4.56 (m, 2H), 3.69 (t, J=7.6 Hz, 2H), 3.38 (t, J=7.3 Hz, 2H), 2.94 (t, J=7.1 Hz, 2H), 2.85 (t , J=7.0 Hz, 2H)
HPLCMS (Method D): [m/z]: 420.3 [M+H] ^+.
1-{1-[2-(1H-1,3-benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl }-1H-Pyrazole-4-carboxamide (Example compound No. 191)

In a similar manner to General Procedure 8, 1-(azetidin-3-yl)-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl}-1H-pyrazole-4 in MeCN (10 ml). Crude with carboxamide (288) (342 mg, 1.21 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (244 mg, 1.27 mmol) and DBU (0.22 ml, 1.5 mmol). This was obtained by further reaction with iron powder (170 mg, 3 mmol) in AcOH (4 ml), basic preparative HPLC followed by flash column chromatography (eluting with a gradient of 0-20% MeOH/DCM). After purification by, the title compound (145 mg, 44%) was obtained as a white solid.

1H-NMR (Methanol-d4,500MHz): d[ppm]=8.37(d, J=5.0Hz, 1H), 8.26(s, 1H), 8.01(s, 1H), 7 0.78-7.73 (m, 1H), 7.52 (dd, J=5.4, 3.0 Hz, 2H), 7.30 (dd, J=7.6, 5.0 Hz, 1H), 7.24-7.18 (m, 2H), 5.56 (t, J=8.2Hz, 1H), 5.06 (m, 1H), 3.86 (td, J=7.3, 1) .6 Hz, 2H), 3.64-3.58 (m, 2H), 3.11-3.07 (m, 3H), 3.03-2.92 (m, 3H), 2.69 (m. , 1H), 2.02 (m, 1H)
HPLC MS (Method C): [m/z]: 428.2 [M+H] ^+.
General scheme 18 above:
tert-Butyl 2-(cyanomethyl)-1H-1,3-benzodiazole-1-carboxylate (296)

2-(1H-1,3-benzodiazol-2-yl)acetonitrile (1 g, 6.36 mmol) and TEA (887 μl, 6.36 mmol) were dissolved in THF (20 ml) and BOC anhydride (1.64 g). , 7.51 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in chloroform and washed with 1M HCl (aq) (50 ml), saturated NaHCO ₃ (aq) (50 ml) and brine (50 ml). The organic phase was dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. Purification by flash chromatography using elution gradient 10-30% EtOAc/heptane gave the title compound (923 mg, 56%) as an orange solid after trituration with DCM/heptane.

_{1H-NMR (CDCl 3, 250MHz} ): d [ppm] = 8.00-7.91 (m, 1H), 7.84-7.74 (m, 1H), 7.48-7.36 (m , 2H), 4.37 (s, 2H), 1.77 (s, 9H)
HPLC MS (Method A): [m/z]: 158.35 [M+H-Boc] ^+.
tert-Butyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1H-1,3-benzodiazole-1-carboxylate (297)

tert-Butyl 2-(cyanomethyl)-1H-1,3-benzodiazole-1-carboxylate (296) (597 mg, 2.32 mmol), TEA (258 mg, 2.55 mmol), Boc ₂ O (557 mg, 2 0.55 mmol) and Pd (10 wt% on carbon, 247 mg, 0.23 mmol) in EtOH (20 ml) were stirred under hydrogen atmosphere for 16 h. The reaction mixture was filtered through a Celite plug and the residue was rinsed with MeOH and 7N ammonia in MeOH. The combined filtrate was evaporated in vacuo. Purification by flash chromatography using elution gradient 0-60% EtOAc/heptane gave the title compound (748 mg, 89%) as a white solid.

_{1H-NMR (CDCl 3, 250MHz} ): d [ppm] = 7.99-7.90 (m, 1H), 7.75-7.67 (m, 1H), 7.39-7.31 (m , 2H), 5.50 (s, 1H), 3.76 (q, J=5.7 Hz, 2H), 3.36 (t, J=5.7 Hz, 2H), 1.73 (s, 9H). ), 1.43 (s, 9H)
HPLCMS (Method A): [m/z]: 362.1 [M+H] ^+.
Ethyl 3-(bromomethyl)-1-methyl-1H-pyrazole-5-carboxylate (298)

Ethyl 1,3-dimethyl-1H-pyrazole-5-carboxylate (433 mg, 2.57 mmol), NBS (0.623 g, 3.5 mmol) and AIBN (40 mg) in DCE (10 ml) at 1.5 at 80°C. Heated for hours. The reaction mixture was cooled to room temperature and evaporated in vacuo. Purification by flash chromatography with elution gradient 0-10% Et ₂ O/heptane gave the title compound (419 mg, 66%) as a white waxy solid.

_{1H-NMR (CDCl 3, 250MHz} ): d [ppm] = 6.90 (s, 1H), 4.48 (s, 2H), 4.36 (q, J = 7.1Hz, 3H), 4. 18 (s, 3H), 1.40 (t, J=7.1Hz, 3H)
HPLC MS (Method A): [m/z]: 246.75/248.75 [M+H] ^+.
tert-Butyl 2-(2-{[(tert-butoxy)carbonyl]({[5-(ethoxycarbonyl)-1-methyl-1H-pyrazol-3-yl]methyl})amino}ethyl)-1H-1 , 3-Benzodiazale-1-carboxylate (299)

Tert-Butyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1H-1,3-benzodiazole-1-carboxylate (298) (263 mg, 0.73 mmol) in THF (5 ml). ) Was cooled in an ice/water bath. NaBH ₄ (60% in mineral oil, 60 mg, 1.5 mmol) was added and the mixture was stirred for 5 minutes. Ethyl 3-(bromomethyl)-1-methyl-1H-pyrazole-5-carboxylate (297) (90 mg, 0.36 mmol) in THF (2 ml) was added and the mixture was allowed to warm to room temperature and stirred for 10 minutes. . The reaction mixture was quenched by the dropwise addition of water, then further diluted with water and extracted with DCM (3 x 20 ml). Dry the organic extracts combined _(Na 2 _SO 4), filtered and evaporated in vacuo. Purification by flash chromatography with elution gradient 0-80% EtOAc/Heptane gave the title compound (126 mg, 66%) as a colorless oil.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=7.68-7.62 (m, 1H), 7.32-7.27 (m, 1H), 7.18-7.13 (m , 2H), 6.43 (s, 1H), 5.26 (s, 2H), 4.19 (q, J=7.1Hz, 2H), 4.09-4.06 (m, 2H), 4.05 (s, 3H), 3.18 (dd, J = 8.4, 6.8Hz, 2H), 1.39 (s, 18H), 1.23 (t, J = 7.1Hz, 3H) )
HPLC MS (Method A): [m/z]: 528.2 [M+H] ^+.
3-({[(tert-butoxy)carbonyl](2-{1-[(tert-butoxy)carbonyl]-1H-1,3-benzodiazol-2-yl}ethyl)amino}methyl)-1- Methyl-1H-pyrazole-5-carboxylic acid (300)

In a manner similar to General Procedure 5, tert-butyl 2-(2-{[(tert-butoxy)carbonyl]({[5-(ethoxycarbonyl)-1-methyl) in THF (5 ml) and water (5 ml). -1H-pyrazol-3-yl]methyl})amino}ethyl)-1H-1,3-benzodiazar-1-carboxylate (299) (126 mg, 0.24 mmol) and LiOH (17 mg, 0.72 mmol). This gave the title compound (152 mg) as a pale yellow oil.

HPLCMS (Method A): [m/z]: 500.15 [M+H] ^+.
tert-butyl 2-(2-{[(tert-butoxy)carbonyl][(5-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1-methyl-1H-pyrazol-3-yl) Methyl]amino}ethyl)-1H-1,3-benzodiazol-1-carboxylate (301)

In a manner similar to general procedure 6 tert-butyl 2-(2-{[(tert-butoxy)carbonyl]({[5-(ethoxycarbonyl)-1-methyl-1H-pyrazole- in DCM (10 ml). 3-yl]methyl})amino}ethyl)-1H-1,3-benzodiazar-1-carboxylate (300) (130 mg, 0.26 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride Salt (A2) (57 mg, 0.29 mmol), DIPEA (150 μl, 0.86 mmol) and HATU (119 mg, 0.31 mmol) gave the crude title compound (317 mg, purity 30%), which is to be purified. Used in the next step without.

HPLC MS (Method A): [m/z]: 608.2 [M+H] ^+.
3-({[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}methyl)-N-[(3-fluoropyridin-2-yl)methyl]-1-methyl-1H -Pyrazole-5-carboxamide (Example compound No. 220)

In a similar manner to general procedure 2 for 15 min at 60° C. in tert-butyl 2-(2-{[(tert-butoxy)carbonyl][(5-{[(3-fluoropyridine- 2-yl)methyl]carbamoyl}-1-methyl-1H-pyrazol-3-yl)methyl]amino}ethyl)-1H-1,3-benzodiazol-1-carboxylate (301) (30%, 317 mg) , 0.16 mmol) and 12M HCl (0.63 ml) to give the title compound (44 mg, 69%) as a white solid after purification by basic preparative HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.93 (m, 1H), 8.34 (dt, J=4.6, 1.4 Hz, 1H), 7.72-7. 63 (m, 1H), 7.56 (m, 1H), 7.52 (dd, J=7.0, 1.4 Hz, 1H), 7.43-7.33 (m, 1H), 7. 21-7.11 (m, 2H), 6.71 (s, 1H), 5.41 (s, 2H), 4.57-4.49 (m, 2H), 4.00 (s, 3H) , 3.05-2.96 (m, 4H)
HPLC MS (Method C): [m/z]: 408.1 [M+H] ^+.
General scheme 19 above
Methyl 2-bromo-1-methyl-1H-imidazole-4-carboxylate (302)

NBS (8.25 g, 46.38 mmol) was added to a stirred solution of methyl 1-methyl-1H-imidazole-4-carboxylate (5 g, 46.38 mmol) in THF (100 ml). The reaction mixture was allowed to stir at room temperature for 72 hours. The mixture was concentrated, the crude residue was dissolved in EtOAc (80 ml) and washed with sat. Na ₂ S ₂ O ₃ (100 ml) and about pH 12 solution of NaOH (50 ml). NaOH solution 1: 4IPA: CHCl3 (5 × 10ml) and extracted with, the organic layers were combined, dried over MgSO _4, filtered, and concentrated to give the crude product. Purification by column chromatography using a gradient of 0-100% EtOAc/heptane gave the purified product, which was dissolved in pH -12 solution of NaOH (50 ml) and extracted with DCM. The organic layers were combined, dried over MgSO ₄ , filtered and concentrated to give the title compound (5.58 g, 71%) as a white solid.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.08 (s, 1H), 3.74 (s, 3H), 3.63 (s, 3H).
HPLC MS (Method A): [m/z]: 218.8, 220.75 [M+H] ^+.
Methyl 2-formyl-1-methyl-1H-imidazole-4-carboxylate (303)

To a stirred solution of methyl 2-bromo-1-methyl-1H-imidazole-4-carboxylate (302) (200 mg, 0.91 mmol) at −40° C. in N ₂ purge in THF (1 ml) was added 2M iPrMgCl(3 in THF. 0.31 ml, 6.62 mmol) was added dropwise. After 20 minutes, the reaction was cooled to −78° C. and DMF (1.08 ml, 13.96 mmol) was added dropwise. The reaction was allowed to warm to room temperature and after 40 minutes the reaction was quenched with saturated NaHCO ₃ (10 ml) to give a thick white emulsion. The product was extracted with EtOAc (5 x 10 ml). The combined organic layers were dried over MgSO _4, filtered, and concentrated to obtain crude product. Purification by silica flash column chromatography using a gradient of 0-70% EtOAc/heptane gave the title compound (128 mg, 66%) as a white solid.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=9.74 (d, J=0.7 Hz, 1H), 8.26 (s, 1H), 3.96 (s, 3H), 3 .80 (s, 3H)
HPLCMS (Method A): [m/z]: 168.9 [M+H] ^+.
Methyl 2-(1-hydroxy-2-nitroethyl)-1-methyl-1H-imidazole-4-carboxylate (304)

To a stirred solution of methyl 2-formyl-1-methyl-1H-imidazole-4-carboxylate (303) (523 mg, 1.47 mmol), MeOH (12 ml) and nitromethane (78.9 μl, 1.47 mmol), 1M NaOH. The solution (12 ml) was added dropwise and the reaction was allowed to warm to room temperature for the duration of the experiment.

After 1 hour, the solution was acidified with 2M HCl to about pH 4 and concentrated to remove methanol. The aqueous layer was extracted with 1:4 IPA/CHCl ₃ (4×10 ml) and the combined organic layers were dried over MgSO ₄ , filtered and concentrated to give the crude product, which was 0-80% EtOAc. Purification by silica flash column chromatography using a gradient of /heptane gave the final product (165 mg, 36%) as an off-white oil.

1H-NMR (DMSO-d6, 500MHz): d [ppm] = 7.94 (s, 1H), 6.35 (d, J = 7.7Hz, 1H), 5.40 (m, 1H), 5 .13 (dd, J=13.3, 4.0 Hz, 1H), 4.90 (dd, J=13.3, 9.4 Hz, 1H), 3.75 (s, 3H), 3.73( s, 3H)
HPLC MS (Method A): [m/z]: 229.9 [M+H] ^+.
Methyl 1-methyl-2-[(E)-2-nitroethenyl]-1H-imidazole-4-carboxylate (305)

A stirred solution of methyl 2-(1-hydroxy-2-nitroethyl)-1-methyl-1H-imidazole-4-carboxylate (304) (197 mg, 0.64 mmol) and acetic anhydride (3.5 ml) was brought to 45°C. Heated. After 4 hours, the reaction was concentrated to give a yellow residue that was partitioned between saturated NaHCO ₃ (20 ml) and EtOAc (20 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (4 x 5 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated to give the crude product which was purified by silica flash column chromatography using a gradient of 20-100% EtOAc/heptane to give the required product ( 97 mg, 60%) was obtained as a yellow solid.

1H-NMR (DMSO-d6,500MHz): d[ppm]=8.19 (s, 1H), 8.02-7.93 (m, 2H), 3.89 (s, 3H), 3.78. (S, 3H)
HPLCMS (Method A): [m/z]: 211.9 [M+H] ^+.
Methyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1-methyl-1H-imidazole-4-carboxylate (306)

Methyl 1-methyl-2-[(E)-2-nitroethenyl]-1H-imidazole-4-carboxylate (305) (110 mg, 0.44 mmol), di-tert-butyl dicarbonate (386.5 mg, 1. 77 mmol) and EtOH (5 ml) in a stirred N ₂ purge solution of Pd/C (10%) (47.1 mg, 0.04 mmol). The reaction was purged with N ₂ followed by H ₂ (×3). After 48 hours, the reaction was filtered under vacuum through glass fiber paper with methanol (20 ml) to wash the filter cake and the filtrate was concentrated to give a crude product. The crude product was purified by flash column chromatography (eluting with a gradient of 0-8% MeOH/DCM) to give the purified product (75 mg, 26%) as a yellow solid.

HPLCMS (Method A): [m/z]: 284 [M+H] ^+.
2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1-methyl-1H-imidazole-4-carboxylic acid (307)

In a manner similar to General Procedure 5, methyl 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1-methyl-1H-imidazol-4-in THF (20 ml) and water (10 ml). The carboxylate (306) (0.5 g, 0.79 mmol) and LiOH (0.19 g, 7.94 mmol) gave the crude product as a yellow solid (0.703 g, quantitative).

HPLCMS (Method A): [m/z]: 270.05 [M+H] ^+.
tert-Butyl N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1-methyl-1H-imidazol-2-yl)ethyl]carbamate (308)

In a similar manner to general procedure 6, 2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1-methyl-1H- in THF (20 ml) and DMF (5 ml) for 3 hours at room temperature. Imidazole-4-carboxylic acid (307) (0.703 g, 0.79 mmol), HATU (0.604 g, 1.59 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (0. After purification by flash column chromatography (eluting with a gradient of 0-9% MeOH/DCM) by 316 g, 1.58 mmol) and DIPEA (0.968 ml, 5.56 mmol) the title compound (0.092 g, 30%). Was obtained as a yellow solid.

HPLC MS (Method A): [m/z]: 378.15 [M+H] ^+.
2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1-methyl-1H-imidazol-4-carboxamide (309)

In a manner similar to General Procedure 2 tert-butyl N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1 in MeOH (4 ml) at 40° C. for 2 hours. - methyl -1H- imidazol-2-yl) ethyl] carbamate (308) (94mg, 0.25mmol) and 12M HCl (0.415ml, by 4.98 mmol), using _{7M NH 3 / MeOH (× 3} ) After running through the column, the product (9 mg, 13%) was obtained as a brown solid.

HPLC MS (Method D): [m/z]: 278.05 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1-methyl-1H-imidazole- 4-carboxamide (Example compound No. 210)

2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1-methyl-1H-imidazole in MeOH (2 ml) for 72 h in a manner similar to general procedure 3. -4-carboxamide (309) (9 mg, 0.032 mmol), anhydrous MgSO ₄ (150 mg), 1H-benzimidazole-2-carbaldehyde (6.2 mg, 0.042 mmol) and DIPEA (11.3 μl, 0.065 mmol). ), followed by addition of NaBH ₄ (1.8 mg, 0.049 mmol), after purification by flash column chromatography using a gradient of 0 to 50% MeOH / DCM, the title compound (4.1 mg, 30%) Was obtained as a brown solid.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.18 (d, J=4.7 Hz, 1H), 7.49-7.44 (m, 1H), 7.44 (s, 1H). , 7.42-7.37 (m, 2H), 7.28-7.22 (m, 1H), 7.11-7.06 (m, 2H), 4.63 (s, 2H), 3 .97 (s, 2H), 3.53 (s, 3H), 2.97 (t, J=6.6Hz, 2H), 2.81 (t, J=6.6Hz, 2H)
HPLC MS (Method A): [m/z]: 408.1 [M+H] ^+.
General scheme 20 above:
Ethyl 1-(cyanomethyl)-5-methyl-1H-imidazole-4-carboxylate (310)

To a stirred solution of NaH (60% in oil) (0.856 g, 21.41 mmol) in DMF (10 ml) at 0° C. under N ₂ purge was ethyl 4-methyl-1H-imidazole-5-carboxylate (3 g, 19. A solution of 46 mmol) in DMF (25 ml) was added dropwise. After 10 minutes, bromoacetonitrile (1.63 ml, 23.35 mmol) was added dropwise to the solution to give a red mixture. The reaction was allowed to warm to room temperature. After 16 hours, the reaction was concentrated and the residue was diluted with saturated NaHCO ₃ (40 ml). The solution was extracted with EtOAc (6x20ml), the combined organic layers were washed with brine (4x15ml), dried over over MgSO _4, filtered, and concentrated to give the crude product. Purification by flash column chromatography using a gradient of 0-6% MeOH/DCM gave the title compound (1.3 g, 35%) as an orange solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=7.76 (s, 1H), 5.38 (s, 2H), 4.22 (q, J=7.1 Hz, 2H), 2 .52 (s, 3H), 1.27 (t, J=7.1Hz, 3H)
HPLCMS (Method A): [m/z]: 194 [M+H] ^+.
Ethyl 1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-4-methyl-1H-imidazole-4-carboxylate (311)

Ethyl 1-(cyanomethyl)-5-methyl-1H-imidazole-4-carboxylate (310) (0.72 g, 3.73 mmol), EtOH (20 ml), TEA (0.675 ml, 4.85 mmol) at room temperature. di -tert- butyl dicarbonate (1.06 g, 4.85 mmol) in _{N 2} purge stirred solution of, Pd / C (10%) (0.397g, 0.37mmol) was added. The reaction was purged with N ₂ (×3) followed by H ₂ . After 16 hours, the reaction was filtered through glass fiber paper and the filter cake was washed with 7M NH ₃ /MeOH (40 ml). The filtrate was concentrated to give the crude product which was further purified by flash column chromatography using a gradient of 0-10% MeOH/DCM to give the required product (1.07 g, 84%) as an off-white solid. Was obtained.

1H-NMR (DMSO-d6, 500MHz): d [ppm] = 7.53 (s, 1H), 7.01-6.93 (m, 1H), 4.19 (q, J = 7.1Hz, 2H), 3.97 (t, J=5.9 Hz, 2H), 3.19 (q, J=6.0 Hz, 2H), 2.43 (s, 3H), 1.37-1.32( m, 9H), 1.28-1.23 (m, 3H)
HPLCMS (Method A): [m/z]: 298.1 [M+H] ^+.
Lithium 1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-1H-imidazole-4-carboxylate (312)

Ethyl 1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-1H-imidazole-4-carboxylate (311) (1.07 g, 3.12 mmol), THF (35 ml) and To a stirred solution of water (10 ml) LiOH (0.224 g, 9.36 mmol) was added and the reaction was heated to 50 °C. After 24 hours, the reaction was concentrated to give the product lithium salt (0.670 g) as a yellow solid.

HPLCMS (Method A): [m/z]: 270.05 [M+H] ^+.
tert-Butyl N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-5-methyl-1H-imidazol-1-yl)ethyl]carbamate (313)

In a similar manner to General Procedure 6, lithium 1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-1H-imidazole-4-carboxylate (312) (0. 670 g, 2.488 mmol), THF (30 ml), DMF (10 ml) and DIPEA (1.733 ml, 9.952 mmol) in HATU (1.419 g, 3.732 mmol) and (3-fluoropyridin-2-yl)methanamine. The dihydrochloride salt (0.743g, 3.732mmol) was added. After 2 hours, the reaction mixture was concentrated, the residue was dissolved in saturated NaHCO ₃ (100 ml) and this was extracted with EtOAc (6×20 ml). The combined organic layers were washed with brine (3×20 ml), dried over MgSO ₄ , filtered and concentrated to give the crude product, which was silica using a gradient of 0-10% MeOH in DCM. Further purification by column chromatography gave an orange oil which was further purified using kp-NH silica column chromatography with a gradient of 0-100% EtOAc in heptane to give the final product (0.320 g, 31%). Was obtained as a yellow oil.

1H-NMR(DMSO-d6,500MHz,) d[ppm]=8.39(d, J=4.6Hz, 1H), 8.22(t, J=5.4Hz, 1H), 7.70( t, J=9.3 Hz, 1H), 7.54 (s, 1H), 7.45-7.37 (m, 1H), 6.98 (t, J=5.6 Hz, 1H), 4. 60 (d, J=4.4 Hz, 2H), 3.96 (t, J=6.0 Hz, 2H), 3.19 (q, J=5.9 Hz, 2H), 2.44 (s, 3H) ), 1.39-1.20 (m, 9H)
HPLC MS (Method A): [m/z]: 378.05 [M+H] ^+.
1-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-methyl-1H-imidazole-4-carboxamide dihydrochloride (314)

In a manner similar to General Procedure 2, tert-butyl N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-5-methyl-1H-imidazol-1-yl). To a stirred solution of ethyl]carbamate (313) (0.320 g, 0.776 mmol) in MeOH (10 ml) was added concentrated HCl (1.293 ml, 15.52 mmol) at room temperature and the reaction was heated to 50 °C. .. After 2 hours, the reaction was concentrated to give the required product (0.294 g, quantitative) as a yellow solid.

1H-NMR (Methanol-d4,500 MHz): d[ppm]=9.03 (s, 1H), 8.54 (s, 1H), 8.06 (s, 1H), 7.75 (s, 1H). ), 4.89 (s, 2H), 4.58 (t, J=6.5 Hz, 2H), 3.48 (t, J=6.4 Hz, 2H), 2.67 (s, 3H).
HPLC MS (Method A): [m/z]: 277.95 [M+H] ^+.
1-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-methyl -1H-imidazole-4-carboxamide (Example compound 219)

In a manner similar to general procedure 8 1-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-methyl-1H-imidazol-4-in MeCN (20 ml). Carboxamide dihydrochloride (314) (0.294 g, 0.77 mmol), DBU (0.347 ml, 2.33 mmol) and N-(2-nitrophenyl)prop-2-enamide (D) (0.332 g, 1). 0.73 mmol), followed by silica column chromatography (0-3% MeOH in DCM), followed by reaction with AcOH (2 ml) and iron powder (0.041 g), followed by basic preparative HPLC, followed by flash column chromatography. After purification by chromatography (kp-NH, gradient 0-5% eluting with MeOH/DCM), the title compound (0.030 g, 30%) was obtained as an off-white solid.

1H-NMR (DMSO-d6, 500MHz): d [ppm] = 12.09 (brs, 1H), 8.39 (d, J = 4.7Hz, 1H), 8.22 (t, J = 5). .5 Hz, 1H), 7.75-7.66 (m, 1H), 7.61 (s, 1H), 7.53-7.35 (m, 3H), 7.13-7.06 (m , 2H), 4.60 (d, J=4.3 Hz, 2H), 3.97 (t, J=6.3 Hz, 2H), 3.00-2.93 (m, 2H), 2.94. -2.88 (m, 2H), 2.84 (t, J=6.3Hz, 2H), 2.47 (s, 3H)
HPLCMS (Method G): [m/z]: 422.1 [M+H] ^+.
General scheme 21 above:
Ethyl 2-{1-[(tert-butoxy)carbonyl]-3-chloroazetidin-3-yl}-5-chloro-1,3-thiazole-4-carboxylate (321)

Ethyl 2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-thiazol-4-carboxylate (161) (1.15 g, 3.68 mmol) and hexachloroethane (0.83 g). 3 mmol) was dissolved in THF (40 ml) and cooled to -78°C. 2M NaHMDS (1.75 ml) was added dropwise and the reaction mixture was left stirring at -78°C for 30 minutes. Further 2M NaHMDS (0.6ml) was added and the reaction mixture was left stirring at -78°C for a further 30 minutes. The reaction was quenched with saturated NH ₄ Cl (aq), warmed to room temperature, diluted with water and extracted with DCM (3×80 ml). Dry the organic extracts combined _(Na 2 _SO 4), filtered and evaporated in vacuo. Two major components were identified in the crude mixture. Purification by flash column chromatography (eluting with a gradient of 2-15% EtOAc/heptane) gave the title compound (456 mg, 32%) as a pale yellow oil.

_{1H-NMR (CDCl 3, 500MHz} ): d [ppm] = 4.72 (d, J = 9.2Hz, 2H), 4.37 (q, J = 7.1Hz, 2H), 4.32 (m , 2H), 1.40 (s, 9H), 1.35 (t, J=7.1Hz, 3H)
HPLC MS (Method A): [m/z]: 402.9 [M+Na] ^+.
2-{1-[(tert-Butoxy)carbonyl]-3-chloroazetidin-3-yl}-5-chloro-1,3-thiazole-4-carboxylic acid (322)

In a manner similar to general procedure 5, ethyl 2-{1-[(tert-butoxy)carbonyl]-3-chloroazetidin-3-yl}-5-chloro-in THF (5 ml) and water (5 ml). 1,3-Thiazol-4-carboxylate (321) (450 mg, 1.18 mmol) and LiOH (0.08 g, 4 mmol) gave the crude title compound (461 mg) as a colorless oil which crystallized on standing. did.

1H-NMR (CDCl ₃ , 250 MHz): d[ppm]=4.76 (dd, J=9.6, 1.0 Hz, 2H), 4.45 (dd, J=9.6, 1.0 Hz, 2H), 1.50 (s, 9H)
HPLC MS (Method A): [m/z]: 378.85 [M+Na] ^+.
tert-Butyl 3-chloro-3-(5-chloro-4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)azetidine-1-carboxylate( 323)

In a similar manner to general procedure 6 2-{1-[(tert-butoxy)carbonyl]-3-chloroazetidin-3-yl}-5-chloro-1,3-thiazole-in DCM (10 ml). 4-Carboxylic acid (322) (460 mg, 1.3 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (311 mg, 1.56 mmol), DIPEA (0.75 ml, 4 mmol) and HATU. The title compound (479 mg, 80%) was obtained after purification by flash column chromatography (eluting with a gradient of 10-50% EtOAc/heptane) by (0.59 g, 2 mmol).

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.34 (dt, J=4.7, 1.1 Hz, 1H), 8.26-8.20 (m, 1H), 7.38. -7.31 (m, 1H), 7.23-7.16 (m, 1H), 4.75 (m, 2H), 4.70 (m, 2H), 4.35 (m, 2H), 1.40 (s, 9H)
HPLCMS (Method A): [m/z]: 460.95 [M+H] ^+.
5-chloro-2-(3-chloroazetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide (324)

In a manner similar to General Procedure 2, tert-butyl 3-chloro-3-(5-chloro-4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1, in MeOH (20 ml). Purify with 3-thiazol-2-yl)azetidine-1-carboxylate (323) (479 mg, 1.04 mmol) and 12M HCl (2 ml) using SCX-2 cartridge, rinse with DCM and MeOH, then After eluting with 7N ammonia in MeOH, the title compound (375 mg, quantitative) was obtained as a white solid.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=9.05-8.96 (m, 1H), 8.40 (dt, J=4.6, 1.4 Hz, 1H), 7. 78-7.66 (m, 1H), 7.48-7.37 (m, 1H), 4.66 (dd, J=5.8, 1.6Hz, 2H), 4.41 (d, J). = 10.5Hz, 2H), 4.07 (d, J = 10.5Hz, 2H)
HPLCMS (Method A): [m/z]: 360.8 [M+H] ^+.
2-{1-[2-(1H-1,3-benzodiazol-2-yl)ethyl]azetidin-3-yl}-5-chloro-N-[(3-fluoropyridin-2-yl)methyl ]-1,3-Thiazol-4-carboxamide (Example Compound No. 209) and 2-{1-[2-(1H-1,3-benzodiazol-2-yl)ethyl]-3-hydroxyazetidine -3-yl}-5-chloro-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazol-4-carboxamide (Example compound No. 211)

In a manner similar to general procedure 8, 5-chloro-2-(3-chloroazetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1 in MeCN (20 ml). ,3-thiazole-4-carboxamide (324) (375 mg, 1.04 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (219 mg, 1.14 mmol) and DBU (0.17 ml, 1). .14 mmol) gave a crude mixture which was further reacted with iron powder (0.2 g) in AcOH (5 ml). Purification by basic preparative HPLC, followed by flash column chromatography (eluting with a gradient of 0-20% MeOH/DCM) gave the title compound (Example Compound #209) (60 mg, 14%) as a white solid. It was

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.14 (s, 1H), 8.77 (t, J=5.6 Hz, 1H), 8.38 (dt, J=4. 6,1.3 Hz, 1H), 7.75-7.67 (m, 1H), 7.56-7.37 (m, 3H), 7.12 (dd, J=5.9, 2.6 Hz). , 2H), 4.66-4.60 (m, 2H), 3.89 (ddd, J=13.1, 7.4, 5.6 Hz, 1H), 3.61 (t, J=7. 2 Hz, 2H), 2.94-2.88 (m, 2H), 2.87-2.81 (m, 2H). One CH ₂ signal is obscured by water peak.

HPLCMS (Method C): [m/z]: 471.1 [M+H] ^+.
The by-product was isolated by basic preparative HPLC to give 2-{1-[2-(1H-1,3-benzodiazol-2-yl)ethyl]-3-hydroxyazetidin-3-yl}-5. -Chloro-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide (Example compound No. 211) (2 mg) was obtained as a white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.16 (s, 1H), 8.86 (t, J=5.5 Hz, 1H), 8.35 (dt, J=4. 6,1.4 Hz, 1H), 7.74-7.67 (m, 1H), 7.54-7.48 (m, 1H), 7.44-7.34 (m, 2H), 7. 15-7.07 (m, 2H), 4.65 (d, J=5.5Hz, 2H), 3.70 (d, J=8.3Hz, 2H), 3.43 (d, J=8) .3 Hz, 2H), 3.01 (t, J=7.2 Hz, 2H), 2.87 (t, J=7.2 Hz, 2H)
HPLC MS (Method C): [m/z]: 487.1 [M+H] ^+.
General scheme 22 above:
tert-Butyl (1R,5S,6S)-6-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (325)

In a manner similar to general procedure 12, (1R,5S,6S)-3-[(tert-butoxy)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid in THF (15 ml). (1 g, 4.4 mmol), TEA (1.04 ml, 0.01 mol), isobutyl chloroformate (0.86 ml, 0.01 mol) and NH ₃ 28% aqueous solution (1.33 ml, 0.07 mol) gave crude title. The product (1.20 g) was obtained as a pale yellow solid. This material was used directly in the next step.

HPLC MS (Method A): [m/z]: 249.05 [M+Na] ^+.
tert-Butyl (1R,5S,6S)-6-carbamothioyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (326)

In a manner similar to general procedure 11, tert-butyl (1R,5S,6S)-6-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (325) (325) (in DCM (40 ml). 1.2 g, 5.3 mmol) and Lawesson's reagent (1.18 g, 2.9 mmol) after purification by flash column chromatography using a gradient elution of 0-10% EtOAc/heptane, the title compound (939 mg, 73%). Was obtained as a white foam.

HPLC MS (Method A): [m/z]: 242.95 [M+H] ^+.
tert-Butyl (1R,5S,6R)-6-[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (327 )

In a manner similar to general procedure 1, tert-butyl(1R,5S,6S)-6-carbamothioyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (326 in EtOH (20 ml). ) (939 mg, 3.87 mmol), ethyl 3-bromo-2-oxopropanoate (0.53 ml, 4 mmol) and CaCO ₃ (0.21 g, 2 mmol) for isocratic elution of 30% EtOAc/heptane. After purification by flash column chromatography used, followed by a second flash column chromatography with gradient elution from 0-40% EtOAc/heptane, the title compound (546 mg, 42%) was obtained as a colorless residue.

HPLC MS (Method A): [m/z]: 339.1 [M+H] ^+.
2-[(1R,5S,6R)-3-[(tert-butoxy)carbonyl]-3-azabicyclo[3.1.0]hexan-6-yl]-1,3-thiazole-4-carboxylic acid ( 328)

In a manner similar to general procedure 5, tert-butyl (1R,5S,6R)-6-[4-(ethoxycarbonyl)-1,3-thiazol-2-yl in THF (20 ml) and water (10 ml). ]-3-Azabicyclo[3.1.0]hexane-3-carboxylate (327) (546 mg, 1.61 mmol) and LiOH (0.12 g, 5 mmol) gave the crude title compound (500 mg, 1.61 mmol). Obtained as a pale yellow oil, which was used in the next step without purification.

HPLCMS (Method A): [m/z]: 311.1 [M+H] ^+.
tert-Butyl (1R,5S,6S)-6-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)-3-azabicyclo[3. 1.0]Hexane-3-carboxylate (329)

In a manner similar to general procedure 6, 2-[(1R,5S,6R)-3-[(tert-butoxy)carbonyl]-3-azabicyclo[3.1.0]hexane-6 in DCM (30 ml). -Yl]-1,3-thiazol-4-carboxylic acid (328) (500 mg, 1.61 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (352.7 mg, 1.77 mmol) ), DIPEA (0.93 ml, 5.31 mmol) and HATU (0.74 g, 1.93 mmol) using flash column chromatography eluting with a gradient of 20-100% EtOAc/heptane to give the title compound ( 650 mg, 96%) was obtained as a colorless foam.

HPLCMS (Method A): [m/z]: 419.1 [M+H] ^+.
2-[(1R,5S,6S)-3-Azabicyclo[3.1.0]hexan-6-yl]-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole- 4-carboxamide (330)

In a manner similar to General Procedure 4, tert-butyl(1R,5S,6S)-6-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1, in MeOH (20 ml). 3-Thiazol-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (329) (624 mg, 1.49 mmol) and 12M HCl (2 ml) with SCX-2 cartridge. After purification, rinsing with DCM and MeOH, then eluting with 7N ammonia in MeOH, the title compound (475 mg, 83%) was obtained.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.65 (t, J=5.6 Hz, 1H), 8.39 (dt, J=4.6, 1.3 Hz, 1H), 8.03 (s, 1H), 7.75-7.69 (m, 1H), 7.45-7.39 (m, 1H), 4.67-4.63 (m, 2H), 3. 05 (m, 3H), 2.78 (d, J = 11.4Hz, 2H), 2.38 (t, J = 3.3Hz, 1H), 2.03-2.00 (m, 2H)
HPLC MS (Method A): [m/z]: 319.05 [M+H] ^+.
2-[(1R,5S,6S)-3-(1H-1,3-benzodiazol-2-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl]-N-[( 3-Fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide (331)

In a similar manner to general procedure 3 for 18 hours at room temperature in 2-[(1R,5S,6S)-3-azabicyclo[3.1.0]hexan-6-yl]-N- in MeOH (10 ml). [(3-Fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide (330) (200 mg, 0.63 mmol), 1H-1,3-benzodiazol-2-carbaldehyde (110). The residue was worked up in 1:1 DMSO/MeCN by adding .17 mg, 0.75 mmol), DIPEA (0.33 ml, 2 mmol) and MgSO ₄ (300 mg), followed by NaBH ₄ (48 mg, 1.3 mmol). After saturating and subsequent rinsing with MeOH, the title compound (62 mg, 22%) was obtained as a pale yellow solid.

1H-NMR (DMSO-d6,500MHz): d[ppm]=12.17(s, 1H), 8.63(t, J=5.7Hz, 1H), 8.40(d, J=4. 6 Hz, 1 H), 8.04 (s, 1 H), 7.76-7.67 (m, 1 H), 7.55 (d, J=7.8 Hz, 1 H), 7.46 (d, J= 7.8 Hz, 1 H), 7.44-7.39 (m, 1 H), 7.20-7.09 (m, 2 H), 4.66 (d, J=4.9 Hz, 2 H), 3. 91 (s, 2H), 3.15 (d, J=9.1 Hz, 2H), 2.96 (t, J=2.8 Hz, 1H), 2.66-2.60 (m, 2H), 2.14-2.10 (m, 2H)
HPLC MS (Method C): [m/z]: 449.1 [M+H] ^+.
2-[(1R,5S,6S)-3-(1H-1,3-benzodiazol-2-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl]-N-[( 3-fluoropyridin-2-yl)methyl]-1,3-thiazol-4-carboxamide trihydrochloride (Example compound 213)

2-[(1R,5S,6S)-3-(1H-1,3-benzodiazol-2-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl]-N-[( 3-Fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide (331) (20 mg, 0.44 mmol) was suspended in MeOH (3 ml) and treated with 12M HCl (0.5 ml). Dissolved. The mixture was stirred for 1 hour and evaporated in vacuo to give the title compound (25mg, quantitative) as a yellow solid.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.58-8.55 (m, 1H), 8.19-8.13 (m, 1H), 8.05 (s, 1H), 7 .86-7.78 (m, 3H), 7.66-7.61 (m, 2H), 4.90 (s, 2H), 4.52 (s, 2H), 3.60-3.52. (M, 2H), 3.22-3.13 (m, 2H), 3.11 (t, J=3.1Hz, 1H), 2.43 (s, 2H)
HPLC MS (Method C): [m/z]: 449.1 [M+H] ^+.
2-[(1R,5S,6S)-3-[2-(1H-1,3-benzodiazol-2-yl)ethyl]-3-azabicyclo[3.1.0]hexan-6-yl] -N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide (Example compound 218)

In a similar manner to General Procedure 8, 2-[(1R,5S,6S)-3-Azabicyclo[3.1.0]hexan-6-yl]-N-[(3-fluoro) in MeCN (15 ml). Pyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide (330) (264 mg, 0.83 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (175 mg, 0. 91 mmol) and DBU (0.14 ml, 0.91 mmol) afforded the crude intermediate which was further reacted with iron powder (180 mg, 3.2 mmol) in AcOH (5 ml) for continuous flash chromatography (0 to 0). After purification by basic preparative HPLC and flash column chromatography (eluting with a gradient of 0-5% MeOH/DCM), the title compound (4 mg, 1%) is a colorless residue. Was obtained as.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.38 (d, J=4.7 Hz, 1H), 7.94 (s, 1H), 7.61 (ddd, J=9.7, 8.4, 1.2 Hz, 1H), 7.53 (m, 2H), 7.43-7.38 (m, 1H), 7.22 (m, 2H), 4.77 (d, J= 1.5Hz, 2H), 3.30 (m, 2H), 3.09 (m, 2H), 3.01 (m, 2H), 2.66 (m, 1H), 2.58 (m, 2H) ), 2.15 (s, 2H)
HPLC MS (method C): [m/z]: 463.1 [M+H] ^+.
General scheme 23

2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl](methyl)amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]- 1,3-Oxazole-4-carboxamide (Example compound No. 223)

2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl in DMF (1 ml) ]-1,3-Oxazole-4-carboxamide (Example Compound No. 127) (59 mg, 0.14 mmol) and TEA (60 μl, 0.43 mmol) were stirred at room temperature for 1 hour. MeI (8.9 μl, 0.14 mmol) was added and stirred at room temperature for 24 hours. The reaction mixture was re-treated with MeI (62.9 μl, 0.79 mmol) and TEA (80 μl, 0.58 mmol) and left stirring at room temperature for 2 days. The mixture was vigorously decompressed in vacuo to give a yellow oil (200 mg) which was subjected to basic preparative HPLC followed by kp-NH column chromatography (eluting with a gradient of 0-10% MeOH/DCM) and flash. Purification by column chromatography (eluting with a gradient of 0-20% MeOH/DCM) gave the title compound (13 mg, 21%) as an off-white solid.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.34-8.29 (m, 1H), 8.15 (s, 1H), 7.61-7.54 (m, 1H), 7 .44 (br s, 2H), 7.38-7.33 (m, 1H), 7.19-7.13 (m, 2H), 4.69 (d, J=1.6Hz, 2H), 3.09-3.04 (m, 2H), 3.04-2.99 (m, 2H), 2.98-2.91 (m, 4H), 2.39 (s, 3H)
HPLC MS (Method G): [m/z]: 423.1 [M+H] ^+.
General Scheme 25 above:
tert-Butyl 3-[(3-hydroxy-1-methoxy-1-oxopropan-2-yl)carbamoyl]azetidine-1-carboxylate (339)

A stirred solution of serine methyl ester hydrochloride (1:1) (2.3 g, 14.78 mmol) and TEA (2.27 ml, 16.26 mmol) in DCM (150 ml) was cooled to 0°C. 1-[(tert-Butoxy)carbonyl]azetidine-3-carboxylic acid (2.97 g, 14.78 mmol) was added, followed by DCC (3.36 g, 16.26 mmol) in portions, then the reaction. Was allowed to warm to room temperature. After 24 hours, the mixture was concentrated and dissolved in EtOAc (about 250 ml). The reaction mixture was left stirring at 50° C. for 45 minutes. Then, the precipitate was filtered off and the filtrate was concentrated to give a crude product as a white solid. Purification by flash column chromatography using 100% TBME followed by DCM/MeOH gradient elution gave the title compound (4.5 g, 91%) as a yellow solid.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=6.75 (d, 1H), 4.66 (dt, 1H), 4.14-4.02 (m, 4H), 3.99( dd, 1H), 3.88 (d, 1H), 3.77 (s, 3H), 3.29 (ddd, 1H), 1.42 (s, 9H)
HPLC MS (Method A): [m/z]: 246.95 [M- ^t Bu] ^+.
Methyl 2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-4,5-dihydro-1,3-oxazol-4-carboxylate (340)

In a similar manner to general procedure 14 tert-butyl 3-[(3-hydroxy-1-methoxy-1-oxopropan-2-yl)carbamoyl]azetidine-1-carboxylate (339) in DCM (120 ml). (4.5 g, 13.4 mmol) and DAST (2.3 ml, 17.42 mmol) gave the title compound (3.3 g, 78%) as a pale yellow oil. The compound was used in the next step without further purification.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=4.78 (m, 1H), 4.60-4.53 (m, 1H), 4.47 (m, 1H), 4.12 ( m, 4H), 3.80 (s, 3H), 3.48-3.36 (m, 1H), 1.43 (s, 9H).
Methyl 2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-oxazole-4-carboxylate (341)

In a similar manner to general procedure 15 methyl 2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-4,5-dihydro-1,3-oxazol-4- in DCM (25 ml). Carboxylate (340) (3.3 g, 10.45 mmol), DBU (2.21 ml, 14.77 mmol) and bromo(trichloro)methane (2.57 ml, 26.12 mmol) in 0-10% MeOH in DCM. After purification by flash column chromatography using a gradient, the title compound (2.3g, 70%) was obtained as a yellow oil.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.21 (s, 1H), 4.30-4.24 (m, 4H), 3.96-3.89 (m, 4H), 1.44 (s, 9H)
HPLC MS (method A): [m/z]: 305.00 [M+Na] ^+.
2-{1-[(tert-Butoxy)carbonyl]azetidin-3-yl}-1,3-oxazole-4-carboxylic acid (342)

In a manner similar to general procedure 5, methyl 2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1, in THF (35 ml) and water (8.5 ml) at room temperature for 4 hours. 3-Oxazole-4-carboxylate (341) (2.3 g, 7.33 mmol) and LiOH (0.26 g, 0.01 mol) gave the title compound (2.0 g, 86%) as a pale yellow oil. It was The crude material was used in the next step without further purification.

HPLCMS (Method A): [m/z]: 290.95 [M+Na] ^+.
2-{1-[(tert-Butoxy)carbonyl]azetidin-3-yl}-1,3-oxazole-4-carboxylic acid (343)

In a similar manner to general procedure 6 for 48 h at room temperature in tert-butyl 3-{4-[(pyridin-2-ylmethyl)carbamoyl]-1,3-oxazol-2-yl}azetidine in DMF (10 ml). -1-carboxylate (342) (1 g, 3.17 mmol), pyridin-2-ylmethanamine (0.343 g, 3.17 mmol), TEA (0.42 ml, 3.17 mmol) and HATU (1.81 g, After purification by flash column chromatography (eluting with a gradient of 40-80% EtOAc/heptane) by 4.75 mmol), the title compound (1.07 g, 32%) was obtained as a brown oil.

1H-NMR (CDCl ₃ , 500 MHz): d[ppm]=8.55 to 8.51 (m, 1H), 8.11 (s, 1H), 7.84 (s, 1H), 7.61( td, J=7.7, 1.8 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.15 (dd, J=7.4, 4.9 Hz, 1H), 4 .67 (d, J=5.5 Hz, 2H), 4.22 (t, J=8.8 Hz, 2H), 4.16 (dd, J=8.6, 6.2 Hz, 2H), 3. 86-3.78 (m, 1H), 1.39 (s, 9H)
HPLC MS (Method A): [m/z]: 359.10 [M+H] ^+.
tert-Butyl 3-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-oxazol-2-yl)azetidine-1-carboxylate (344)

2-{1-[(tert-Butoxy)carbonyl]azetidin-3-yl}-1,3-oxazole-4-carboxylic acid in THF (50 ml) and DMF (10 ml) in a similar manner to general procedure 6. (342) (1.0 g, 3.48 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (0.83 g, 4.17 mmol), DIPEA (2.42 ml, 13.91 mmol). And HATU (1.59 g, 4.17 mmol) after purification by flash column chromatography (eluting with a gradient of 20-100% EtOAc/heptane) to give the title compound (1.56 g, 90%) as a yellow oil. It was

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.68-8.54 (m, 2H), 8.38 (d, J=4.6 Hz, 1H), 7.75-7. 63 (m, 1H), 7.40 (m, 1H), 4.66-4.57 (m, 2H), 4.31-4.15 (m, 2H), 4.11-3.95( m, 3H), 1.39 (s, 9H)
HPLC MS (Method A): [m/z]: 377.15 [M+H] ^+.
tert-Butyl 3-{4-[(pyridazin-3-ylmethyl)carbamoyl]-1,3-oxazol-2-yl}azetidin-1-carboxylate (345)

In a similar manner to General Procedure 6, 2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-oxazole-4-carboxylic acid (342)(0) in DCM (20 ml). 2.8 g, 2.98 mmol), 1-(pyridazin-3-yl)methanamine (0.42 g, 3.28 mmol, purity 85%), DIPEA (779 μl, 4.47 mmol) and HATU (1.36 g, 3.58 mmol). ) By flash column chromatography (eluted with 50-100% EtOAc/heptane, followed by a gradient of 0-20% MeOH/EtOAc) to give the title compound (0.90 g, 84%) as a brown residue. It was

HPLC MS (method M): [m/z]: 360.00 [M+H] ^+.
2-(azetidin-3-yl)-N-(pyridin-2-ylmethyl)-1,3-oxazole-4-carboxamide (346)

In a similar manner to General Procedure 2 tert-butyl 3-{4-[(pyridin-2-ylmethyl)carbamoyl]-1,3-oxazol-2-yl} in MeOH (20 ml) at 50° C. for 30 minutes. azetidine-1-carboxylate (343) (1.07g, 2.99mmol) and the 12M HCl (2ml), it was purified using SCX-2 cartridge (10 g), rinsed with DCM and MeOH, then, 7N NH ₃ After eluting with /MeOH the title compound (0.457g, 59%) was obtained as a yellow solid. The basic eluent was then concentrated to give the title compound as the free base.

HPLCMS (Method A): [m/z]: 259.00 [M+H] ^+.
2-(azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide dihydrochloride (347)

In a manner similar to General Procedure 2 tert-butyl 3-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-oxazole in MeOH (25 ml) at room temperature for 16 hours. 2-yl)azetidine-1-carboxylate (344) (1.56 g, 3.12 mmol) and concentrated HCl (5.2 ml, 62.51 mmol) gave the title compound (1.31 g, quantitative) as an off-white solid. Was obtained as. The crude material was used in the next step without purification.

HPLC MS (Method A): [m/z]: 277.05 [M+H] ^+.
2-(azetidin-3-yl)-N-(pyridazin-3-ylmethyl)-1,3-oxazole-4-carboxamide (348)

In a similar manner to general procedure 2 for 40 minutes at room temperature in tert-butyl 3-{4-[(pyridazin-3-ylmethyl)carbamoyl]-1,3-oxazol-2-yl}azetidine in DCM (10 ml). 1-carboxylate (345) (900mg, 2.5mmol) and by TFA (10ml, 130.6mmol), and purified using SCX-2 cartridge (10 g), rinsed with DCM and MeOH, then, 7N NH ₃ After eluting with /MeOH the title compound (447 mg, 69%) was obtained as a beige solid. The basic eluent was then concentrated to give the title compound as the free base.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=9.14 (dd, J=4.7, 1.7 Hz, 1H), 8.95 (t, J=6.0 Hz, 1H), 8.60 (s, 1H), 7.67 (dd, J=8.5, 4.7 Hz, 1H), 7.59 (dd, J=8.5, 1.8 Hz, 1H), 4.73 (D, J=6.2 Hz, 2H), 4.13-3.99 (m, 1H), 3.89-3.70 (m, 4H)
HPLC MS (Method M): [m/z]: 260.00 [M+H] ^+.
2-{1-[2-(1H-1,3-benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-(pyridin-2-ylmethyl)-1,3-oxazole-4- Carboxamide (Example compound 207)

In a similar manner to General Procedure 8, 2-(azetidin-3-yl)-N-(pyridin-2-ylmethyl)-1,3-oxazole-4-carboxamide (346) (457 mg, in MeCN (20 ml)). 1.769 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (408 mg, 2.123 mmol) and DBU (0.32 ml, 2.123 mmol) gave a crude intermediate which was flashed. Purified by column chromatography (eluting with a gradient of 0-5% MeOH/DCM). The intermediate was further reacted with iron powder (134 mg) in AcOH (3 ml) to give the title compound (26 mg, 8%) as a white solid after purification by basic preparative HPLC.

1H-NMR (DMSO-d6,500MHz): d[ppm]=8.50(d, J=4.3Hz, 1H), 8.33(s, 1H), 7.80(m, 1H), 7 .50 (s, 2H), 7.40 (d, J=7.9 Hz, 1H), 7.34-7.29 (m, 1H), 7.22-7.16 (m, 2H), 4 .67 (s, 2H), 3.88 (p, J=7.3 Hz, 1H), 3.75 (t, J=8.0 Hz, 2H), 3.54 (t, J=7.5 Hz, 2H), 3.05-2.99 (m, 2H), 2.99-2.93 (m, 2H) HPLC MS (method G): [m/z]: 403.2 [M+H] ^+.
2-{1-[2-(1H-1,3-benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-[(3-fluoropyridin-2-yl)methyl]-1, 3-Oxazole-4-carboxamide (Example compound No. 208)

In a similar manner to general procedure 8 at room temperature for 4 hours 2-(azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3- in MeCN (30 ml). Oxazole-4-carboxamide dihydrochloride (347) (0.657 g, 1.571 mmol), DBU (0.703 ml, 4.713 mmol) and N-(2-nitrophenyl)prop-2-enamide (D)(0). .332 g, 1.728 mmol) afforded the crude intermediate which was purified by flash column chromatography (eluting with a gradient of 0-3% MeOH/DCM) to give a yellow oil (0.778 g). This was further reacted with iron powder (0.191 g) in AcOH (4 ml) at 80° C. for 2 h, flash column chromatography (kp-NH, eluting with a gradient of 0-3% MeOH/DCM) followed by another. After purification by flash column chromatography (eluting with a gradient of 0-20% MeOH/DCM), the title compound (0.072 g, 15%) was obtained as a white solid.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.36 (d, J=4.7 Hz, 1H), 8.32 (s, 1H), 7.62-7.56 (m, 1H). , 7.50 (brs, 2H), 7.41-7.36 (m, 1H), 7.22-7.17 (m, 2H), 4.75 (d, J=1.5Hz, 2H). ), 3.88 (p, J=7.3 Hz, 1H), 3.75 (t, J=8.0 Hz, 2H), 3.53 (t, J=7.5 Hz, 2H), 3.04. -2.99 (m, 2H), 2.99-2.93 (m, 2H)
HPLCMS (Method C): [m/z]: 421.1 [M+H] ^+.
2-{1-[2-(1H-1,3-benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-(pyridazin-3-ylmethyl)-1,3-oxazol-4- Carboxamide (Example compound 244)

In a similar manner to General Procedure 8, 2-(azetidin-3-yl)-N-(pyridazin-3-ylmethyl)-1,3-oxazole-4-carboxamide (348) (440 mg, in MeCN (20 ml)). 1.7 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (326 mg, 1.7 mmol) and DBU (279 μl, 1.87 mmol) gave a crude intermediate which was further AcOH(. Reaction with iron powder (302 mg, 5.41 mmol) in 5 ml) gave the title compound (82 mg, 15%) as a white solid after purification by basic preparative HPLC.

1H-NMR (MeOD, 500 MHz): d[ppm]=9.12 (dd, J=4.5, 2.1 Hz, 1H), 8.36 (s, 1H), 7.76-7.69( m, 2H), 7.51 (s, 2H), 7.24-7.19 (m, 2H), 4.88 (s, 2H), 3.93-3.85 (m, 1H), 3 0.78-3.74 (m, 2H), 3.58-3.53 (m, 2H), 3.07-3.01 (m, 2H), 3.01-2.95 (m, 2H)
HPLCMS (Method B): [m/z]: 404.2 [M+H] ^+.
2-{1-[2-(4-Fluoro-1H-1,3-benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-[(3-fluoropyridin-2-yl)methyl ]-1,3-Oxazole-4-carboxamide (Example compound 239)

In a similar manner to General Procedure 8-2-(azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide in MeCN (30 ml). Bis(trifluoroacetic acid) (347) (700 mg, 1.39 mmol), DBU (1.04 ml, 6.94 mmol) and N-(3-fluoro-2-nitrophenyl)prop-2-enamide (G) ( 292 mg, 1.39 mmol) afforded the crude intermediate which was further reacted with iron powder (173 mg, 3.1 mmol) in AcOH (5 ml) and flash column chromatography (0-8% MeOH/DCM gradient). After purification by elution), the title compound (98 mg, 29%) was obtained as a pale pink solid.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.38 (dt, J=4.6, 1.1 Hz, 1H), 8.35 (s, 1H), 7.62 (ddd, J=) 9.8, 8.4, 1.2 Hz, 1H), 7.41 (dt, J=8.6, 4.5 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7 .18 (td, J=8.1, 4.8 Hz, 1H), 6.95 (dd, J=10.8, 8.0 Hz, 1H), 4.77 (d, J=1.5 Hz, 2H) ), 3.94-3.86 (m, 1H), 3.78 (t, J=7.9 Hz, 2H), 3.57 (t, J=7.5 Hz, 2H), 3.08-3. 0.03 (m, 2H), 3.02-2.97 (m, 2H)
HPLCMS (Method B): [m/z]: 439.2 [M+H] ^+.
2-{1-[2-(4-Fluoro-1H-1,3-benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-(pyridin-2-ylmethyl)-1,3- Oxazole-4-carboxamide (Example compound 258)

In a similar manner to general procedure 8, 2-(azetidin-3-yl)-N-(pyridin-2-ylmethyl)-1,3-oxazole-4-carboxamide (346) (0. 0) in MeCN (30 ml). 88 g, 3.21 mmol), N-(3-fluoro-2-nitrophenyl)prop-2-enamide (G) (0.80 g, 3.53 mmol) and DBU (580 μl, 3.86 mmol) to give the crude intermediate. Obtained which was further reacted with iron powder (0.57 g, 10.24 mmol) in AcOH (16 ml) and flash column chromatography (eluted with a gradient of 0-15% MeOH/hexane) followed by basic fractionation. After purification by preparative HPLC, the title compound (0.59 g, 55%) was obtained as an off-white solid.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.51-8.48 (m, 1H), 8.33 (s, 1H), 7.80 (td, J=7.7, 1. 8 Hz, 1 H), 7.40 (d, J=7.9 Hz, 1 H), 7.34-7.27 (m, 2 H), 7.16 (td, J=8.1, 4.8 Hz, 1 H ), 6.92 (dd, J=10.8, 8.1 Hz, 1H), 4.67 (s, 2H), 3.93-3.83 (m, 1H), 3.75 (t, J). =7.9 Hz, 2H), 3.54 (t, J=7.5 Hz, 2H), 3.05-3.00 (m, 2H), 2.99-2.95 (m, 2H)
HPLCMS (Method C): [m/z]: 421.3 [M+H] ^+.
2-{1-[2-(4-Fluoro-1H-1,3-benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-(pyridazin-3-ylmethyl)-1,3- Oxazole-4-carboxamide (Example compound No. 261)

In a manner similar to general procedure 8, 2-(azetidin-3-yl)-N-(pyridazin-3-ylmethyl)-1,3-oxazole-4-carboxamide (348) (417 mg, in MeCN (50 ml)). 1.61 mmol), N-(3-fluoro-2-nitrophenyl)prop-2-enamide (G) (372 mg, 1.77 mmol) and DBU (264 μl, 1.77 mmol) gave the crude intermediate, which was Was further reacted with iron powder (261 mg, 4.67 mmol) in AcOH (10 ml) to give the title compound (268 mg, 54%) as a white solid after purification by basic preparative HPLC.

1H-NMR (MeOD, 500 MHz): d[ppm]=9.12 (dd, J=4.5, 2.1 Hz, 1H), 8.36 (s, 1H), 7.76-7.70( m, 2H), 7.31 (d, J=8.1Hz, 1H), 7.18 (td, J=8.1, 4.8Hz, 1H), 6.97-6.91 (m, 1H). ), 4.88 (s, 2H), 3.89 (p, J=7.3 Hz, 1H), 3.79-3.74 (m, 2H), 3.58-3.53 (m, 2H). ), 3.06-3.02 (m, 2H), 3.02-2.96 (m, 2H)
HPLCMS (Method B): [m/z]: 422.2 [M+H] ^+.
N-[(3-fluoropyridin-2-yl)methyl]-2-(1-{2-[7-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl]ethyl}azetidine -3-yl)-1,3-oxazole-4-carboxamide (Example compound 273)

In a similar manner to general procedure 8, 2-(azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide in MeCN (18 ml). (347) (393 mg, 1.42 mmol), N-[2-nitro-6-(trifluoromethyl)phenyl]prop-2-enamide (K8) (474 mg, 1.42 mmol, purity 78%) and DBU (0. .23 ml, 1.56 mmol) afforded the crude intermediate which was further reacted with iron powder (280 mg, 5.01 mmol) in AcOH (8 ml) and flash column chromatography (0-20% MeOH/DCM). After purification by gradient elution), the title compound (197 mg, 32%) was obtained as a light brown foam.

1H-NMR (DMSO-d6,500MHz): d[ppm]=12.64 (s, 1H), 8.55 (s, 1H), 8.52 (t, J=5.7Hz, 1H), 8 .39-8.35 (m, 1H), 7.76 (s, 1H), 7.71-7.65 (m, 1H), 7.48-7.43 (m, 1H), 7.43. −7.37 (m, 1H), 7.30-7.26 (m, 1H), 4.66-4.58 (m, 2H), 3.81 (p, J=7.4 Hz, 1H) , 3.63 (t, J=7.5 Hz, 2H), 3.35 (t, J=7.2 Hz, 2H), 2.90 (s, 4H)
HPLC MS (Method D): [m/z]: 489.1 [M+H] ^+.
General scheme 26 above:
2-(3-chloropropyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazole (349)

[2-(Chloromethoxy)ethyl](trimethyl)silane (553 μl, 3.12 mmol) was added to 2-(3-chloropropyl)-1H-1,3-benzodiazole hydrochloride (555 mg, 2.4 mmol) and DIPEA (962 μl, 5.52 mmol) was added to a solution in THF (25 ml). The reaction mixture was stirred at room temperature for 18 hours, then quenched with saturated NaHCO ₃ (aq) and extracted with EtOAc (3×80 ml). The combined organic extracts were washed with brine (50 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo. Purification by flash column chromatography (eluting with a gradient of 0-50% EtOAc/heptane) gave the title compound (571 mg, 73%) as a pale yellow oil.

1H-NMR (CDCl ₃ , 250 MHz): d[ppm]=7.85-7.75 (m, 1H), 7.53-7.44 (m, 1H), 7.38-7.31 (m). , 2H), 5.57 (s, 2H), 3.78 (t, J=6.1 Hz, 2H), 3.60 (dd, J=8.6, 7.7 Hz, 2H), 3.21. (T, J=7.3 Hz, 2H), 2.59-2.44 (m, 2H), 0.96 (dd, J=8.6, 7.7 Hz, 2H), 0.00 (s, 9H)
HPLC MS (method M): [m/z]: 325.50 [M+H] ^+.
Methyl 2-(azetidin-3-yl)-1,3-oxazole-4-carboxylate hydrochloride (350)

In a similar manner to General Procedure 4, methyl 2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-oxazole-4-carboxylate (in 60 mL of MeOH (20 ml) at 60°C. 341) (634 mg, 2.25 mmol) and 12M HCl (0.89 ml) in trituration in DCM/Et ₂ O to give the title compound (201 mg, 41%) as a white solid.

1H-NMR (DMSO-d6, 250MHz): d[ppm]=8.91 (s, 1H), 4.36-4.15 (m, 5H), 3.83 (s, 3H).
HPLC MS (Method M): [m/z]: 183.20 [M+H] ^+.
Methyl 2-{1-[3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl)propyl]azetidin-3-yl}-1,3 -Oxazole-4-carboxylate (351)

Methyl 2-(azetidin-3-yl)-1,3-oxazole-4-carboxylate hydrochloride (350) (300 mg, 1.37 mmol), 2-(3-chloropropyl)-1-{[2-( Trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazole (349) (758 mg, 2.33 mmol), DIPEA (837 μl, 4.8 mmol) and KI (228 mg, 1.37 mmol) in DMF (10 ml). The suspension was stirred at room temperature for 7 days. The reaction was quenched with saturated NaHCO ₃ (aq) and extracted with EtOAc (3 x 50 ml). The combined organic extracts were washed with brine (4 × 50 ml), dried _(Na 2 _SO 4), filtered and evaporated in vacuo. Purification by flash column chromatography (40-100% EtOAc/heptane, followed by elution with a gradient of 2-40% MeOH/EtOAc) gave the title compound (329 mg, 46%, 91% purity) as a yellow residue. .

HPLC MS (Method M): [m/z]: 471.15 [M+H] ^+.
2-{1-[3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl)propyl]azetidin-3-yl}-1,3- Oxazole-4-carboxylic acid (352)

In a manner similar to general procedure 5, 2-{1-[3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzo in THF (10 ml) and water (10 ml). Diazol-2-yl)propyl]azetidin-3-yl}-1,3-oxazol-4-carboxylate (351) (329 mg, 0.7 mmol) and LiOH (50 mg, 2.1 mmol) gave the title compound ( 363 mg, 91%, purity 80%) was obtained as a yellow residue. The compound was used in the next step without purification.

HPLC MS (Method M): [m/z]: 457.10 [M+H] ^+.
N-[(3-fluoropyridin-2-yl)methyl]-2-{1-[3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazole-2 -Yl)propyl]azetidin-3-yl}-1,3-oxazole-4-carboxamide (353)

In a similar manner to General Procedure 6 2-{1-[3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2- in DCM (20 ml). (Il) propyl]azetidin-3-yl}-1,3-oxazole-4-carboxylic acid (352) (363 mg, 0.64 mmol, purity 80%), (3-fluoropyridin-2-yl)methanamine dihydrochloride After purification by (A2) (152 mg, 0.76 mmol), DIPEA (388 μl, 2.23 mmol) and HATU (290 mg, 0.76 mmol) by flash column chromatography (eluting with a gradient of 0-40% MeOH/DCM). , The title compound (302 mg, 84%) was obtained as a pale yellow residue.

HPLC MS (Method M): [m/z]: 565.15 [M+H] ^+.
2-{1-[3-(1H-1,3-benzodiazol-2-yl)propyl]azetidin-3-yl}-N-[(3-fluoropyridin-2-yl)methyl]-1, 3-Oxazole-4-carboxamide (Example compound 233)

TFA (4 ml, 52.23 mmol) was added to N-[(3-fluoropyridin-2-yl)methyl]-2-{1-[3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H. -1,3-Benzodiazol-2-yl)propyl]azetidin-3-yl}-1,3-oxazole-4-carboxamide (353) (300 mg, 0.53 mmol) was added to a solution in DCM (4 ml). did. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the residue basified by addition of 2M NaOH (aq). The mixture was then extracted with 4:1 CHCl ₃ /IPA (4×50 ml). Dry the organic extracts combined _(Na 2 _SO 4), filtered and evaporated in vacuo. The residue was dissolved in a minimum amount of MeOH and loaded onto a SCX-2 cartridge (10g). Rinsed with MeOH cartridge DCM, it was subsequently eluted with _7N NH 3 / MeOH. The basic eluent was evaporated under vacuum. The residue was purified by basic preparative HPLC to give the title compound (75 mg, 33%) as a white solid.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.37 (dt, J=4.6, 1.1 Hz, 1H), 8.33 (s, 1H), 7.61 (ddd, J=) 9.8, 8.4, 1.2 Hz, 1H), 7.50 (s, 2H), 7.41 (dt, J=8.7, 4.4 Hz, 1H), 7.23-7.17. (M, 2H), 4.77 (d, J=1.5 Hz, 2H), 3.93-3.84 (m, 1H), 3.75 (t, J=8.0 Hz, 2H), 3 .53 (t, J=7.5 Hz, 2H), 2.94 (t, J=7.6 Hz, 2H), 2.66-2.60 (m, 2H), 1.97-1.88 ( m, 2H)
HPLCMS (Method B): [m/z]: 435.1 [M+H] ^+.
General Scheme 28 above:
3-{[(tert-butoxy)carbonyl]amino}-3-methylbutanoic acid (360)

A mixture of 1 M KOH (15.19 ml) in 3-amino-3-methylbutanoic acid (1.78 g, 15.19 mmol) and Boc ₂ O (3.48 g, 15.95 mmol) in 1,4-dioxane (30 ml). And stirred at room temperature for 40 hours. The solvent was concentrated and diluted with water (60 ml). 1M LiOH was added to pH 13. The aqueous phase was extracted with Et ₂ O (3×30 ml), then the pH was adjusted to 3 with 2M HCl and extracted with EtOAc (4×60 ml). The combined organic layers were washed with brine (30 ml), dried (Na ₂ SO ₄ ), filtered and evaporated to give the title compound (2.13 g, 65%) as an off-white solid. The compound is used in the next step without further purification.

1H-NMR (CDCl ₃ , 250 MHz): d [ppm] = 5.07 (s, 1H), 2.75 (s, 2H), 1.44 (s, 9H), 1.40 (s, 6H).
3-{[(tert-butoxy)carbonyl]amino}-2,2-dimethylpropanoic acid (361)

1M KOH (52.08 ml, 52.08 mmol) in 1,4 of 3-amino-2,2-dimethylpropanoic acid hydrochloride (4 g, 26.04 mmol) and Boc ₂ O (5.97 g, 27.34 mmol). -Added to the mixture in dioxane (80 ml) and stirred at room temperature for 20 hours. The solvent was concentrated and diluted with water (50 ml). 1M LiOH was added to pH 13. The aqueous phase was extracted with Et ₂ O (3×50 ml), then the pH was adjusted to 3 with 2M HCl and extracted with EtOAc (4×50 ml). The combined organic layers were washed with brine (50 ml), dried (Na ₂ SO ₄ ), filtered and evaporated to give the title compound (5.38 g, 95%) as a white solid. The compound is used in the next step without further purification.

_{1H-NMR (CDCl 3, 250MHz} ): d [ppm] = 5.01 (s, 1H), 3.29-3.18 (m, 2H), 1.45 (d, 9H), 1.23 ( s, 6H)
tert-Butyl N-(1-carbamoyl-2-methylpropan-2-yl)carbamate (362)

TEA (2.82 ml, 20.27 mmol) was ice-cooled with 3-{[(tert-butoxy)carbonyl]amino}-3-methylbutanoic acid (360) (2.59 g, 11.92 mmol) in THF (30 ml). (0° C.) added to the solution. After stirring the reaction mixture for 20 minutes, 2-methylpropyl carbonochloridate (2.78 ml, 17.88 mmol) was added dropwise at 0°C. After stirring the reaction for 1 h, 35% NH ₃ (aq) (3.09 ml, 66.76 mmol) was added dropwise, the reaction was warmed to room temperature and stirred for 18 h. It was added saturated NaHCO ₃ (50ml), the aqueous layer was extracted with DCM (3 × 50ml). The combined organic layers were dried (MgSO _4), filtered to give a pale yellow oil (4.11 g) and evaporated. Purification by flash column chromatography (eluting with a gradient of 0-10% MeOH-DCM) gave the title compound (1.7 g, 55%, 84% pure) as a clear oil which solidified on standing.

_{1H-NMR (CDCl 3, 250MHz} ): d [ppm] = 5.85 (br s, 1H), 5.39 (br s, 1H), 4.89 (br s, 1H), 2.64 (s , 2H), 1.42 (s, 9H), 1.39 (s, 6H)
HPLC MS (Method A): [m/z]: 238.95 [M+Na] ^+.
tert-Butyl N-(2-carbamoyl-2,2-dimethylethyl)carbamate (363)

TEA (5.73 ml, 41.08 mmol) was added to 3-{[(tert-butoxy)carbonyl]amino}-2,2-dimethylpropanoic acid (361) (5.25 g, 24.16 mmol) in THF (50 ml). Add to medium ice cold (0° C.) solution. After stirring the reaction for 20 minutes, 2-methylpropylcarbonochloridate (4.7 ml, 36.3 mmol) was added dropwise at 0°C. After stirring the reaction for 1 h, 35% NH ₃ (aq) (7.48 ml, 135.31 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 22 hours. It was added saturated NaHCO ₃ (100ml), the aqueous layer was extracted with DCM (3 × 150ml). The combined organic layers were dried (MgSO _4), filtered and evaporated to give an off-white semi-solid (6.61 g). Purification by flash column chromatography (eluting with a gradient of 0-10% MeOH/DCM) gave the title compound (3.7 g, 71%) as a white solid.

1H-NMR (CDCl ₃ , 250 MHz): d[ppm]=5.95 (s, 1H), 5.30 (s, 1H), 5.08 (s, 1H), 3.25 (d, J= 6.6Hz, 2H), 1.43 (s, 9H), 1.21 (s, 6H)
HPLC MS (Method A): [m/z]: 239.10 [M+Na] ^+.
tert-Butyl N-(1-carbamothioyl-2-methylpropan-2-yl)carbamate (364)

In a similar manner to General Procedure 11 Lawesson's reagent (1.65 g, 4.08 mmol) and tert-butyl N-(1-carbamoyl-2-methylpropan-2-yl in DCM (50 ml) for 19 h at room temperature. ) Carbamate (362) (1.7 g, 6.6 mmol, 84% purity) after purification by flash column chromatography (eluting with a gradient of 0-50% EtOAc/heptane), the title compound (0.914 g, 60%). ) Was obtained as a yellow oil which solidified on standing.

1H-NMR (MeOD, 250 MHz): d[ppm]=2.91 (s, 2H), 1.43 (s, 9H), 1.38 (s, 6H).
HPLC MS (method A): [m/z]: 232.95 [M+H] ^+.
tert-butyl N-(2-carbamothioyl-2,2-dimethylethyl)carbamate (365)

In a manner similar to general procedure 11, Lawesson's reagent (3.29 g, 8.14 mmol) and tert-butyl N-(2-carbamoyl-2,2-dimethylethyl)carbamate in DCM (65 ml) at room temperature for 24 hours. After purification by flash column chromatography (eluting with a gradient of 0-50% EtOAc-Heptane) by (363) (3.2 g, 14.8 mmol), the title compound (1.67 g, 49%) is obtained as a white solid. Was given.

1H-NMR (MeOD, 250 MHz): d[ppm]=3.35 (s, 2H), 1.44 (s, 9H), 1.25 (s, 6H).
HPLC MS (Method A): [m/z]: 254.95 [M+Na] ^+.
Ethyl 2-(2-{[(tert-butoxy)carbonyl]amino}-2-methylpropyl)-1,3-thiazole-4-carboxylate (366)

In a similar manner to General Procedure 1, tert-butyl N-(1-carbamothioyl-2-methylpropan-2-yl)carbamate (364) (0.91 g, 3.93 mmol) in EtOH (10 ml), Flash column chromatography (eluted with a gradient of 0-100% EtOAc/heptane) by ethyl 3-bromo-2-oxopropanoate (0.64 ml, 4.33 mmol) and CaCO ₃ (0.22 g, 2.16 mmol). After), the title compound (0.285 g, 19%) was obtained as an orange oil.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.42 (s, 1H), 4.29 (q, J=7.2 Hz, 2H), 3.39 (s, 2H), 1 .36 (s, 9H), 1.30 (d, J=7.0Hz, 3H), 1.20 (s, 6H)
HPLCMS (Method A): [m/z]: 329.00 [M+H] ^+.
Ethyl 2-(1-{[(tert-butoxy)carbonyl]amino}-2-methylpropan-2-yl)-1,3-thiazol-4-carboxylate (367)

In a manner similar to General Procedure 1 tert-butyl N-(2-carbamothioyl-2,2-dimethylethyl)carbamate (365) (1.67 g, 7.9 mmol), ethyl 3 in EtOH (20 ml). - bromo-2-oxopropanoate (1.2 ml, 7.9 mmol) and CaCO ₃ a (0.4 g, 3.95 mmol) was stirred at room temperature for 72 hours. The reaction was further treated with MgSO ₄ (0.8g) and CaCO ₃ (0.4g, 3.95mmol) and heated at 80°C for 7 hours. The reaction was cooled and the solvent was evaporated to give a residue which was redissolved in EtOAc (50 ml) and washed with sat. NaHCO ₃ (7 ml). The aqueous layer was extracted with EtOAc (3 × 15ml), the combined organic layers were dried (MgSO _4), filtered and evaporated to give a brown oil (2.61 g). The oil was dissolved in DCM (50 ml), TEA (2.9 ml, 20.58 mmol) was added, followed by dropwise addition of di-tert-butyl dicarbonate (3.74 g, 17.15 mmol) in DCM (20 ml). did. The reaction was stirred at room temperature for 22 hours. The reaction mixture was diluted with DCM (10 ml), to obtain an organic layer was washed with water (20ml), brine (20ml), dried (MgSO _4), filtered and evaporated a brown oil (4.82 g) It was Purification by flash column chromatography (eluted with 0-50% EtOAc-heptane) gave the title compound (1.4 g, 36%) as a yellow oil.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.06 (s, 1H), 5.19 (br s, 1H), 4.40 (q, J=7.1 Hz, 2H), 3.50 (br s, 2H), 1.44 (s, 6H), 1.42 (s, 9H)
HPLCMS (Method A): [m/z]: 329.00 [M+H] ^+.
2-(2-{[(tert-butoxy)carbonyl]amino}-2-methylpropyl)-1,3-thiazole-4-carboxylic acid (368)

In a manner similar to General Procedure 5, ethyl 2-(2-{[(tert-butoxy)carbonyl]amino}-2-methylpropyl) in THF (4 ml) and H ₂ O (2 ml) at room temperature for 5 hours. With -1,3-thiazole-4-carboxylate (366) (0.285 g, 0.867 mmol, purity 85%) and LiOH (88 mg, 3.67 mmol), the title compound (0.215 g, 66%, purity 68). %) was obtained as a dark yellow oil. The compound was used in the next step without further purification.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.35 (s, 1H), 3.38 (s, 2H), 1.43 (s, 9H), 1.21 (s, 6H). )
HPLCMS (Method A): [m/z]: 301.00 [M+H] ^+.
2-(1-{[(tert-butoxy)carbonyl]amino}-2-methylpropan-2-yl)-1,3-thiazole-4-carboxylic acid (369)

In a similar manner to general procedure 5, ethyl (2-(1-{[(tert-butoxy)carbonyl]amino}-2-methylpropane-2- in THF (20 ml) and water (10 ml) at room temperature for 3 hours. Yl)-1,3-thiazole-4-carboxylate (367) (1.4 g, 4.12 mmol) and LiOH (0.49 g, 20.6 mmol) gave the title compound (1.5 g, 98%, purity 83). %) as a yellow oil which solidified on standing. Use without purification.

1H-NMR (DMSO-d6, 250MHz): d[ppm]=8.32 (s, 1H), 6.98-6.88 (m, 1H), 3.18 (d, J=6.5Hz, 2H), 1.34 (s, 9H), 1.32 (s, 6H)
HPLCMS (Method A): [m/z]: 301.05 [M+H] ^+.
tert-butyl N-[1-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)-2-methylpropan-2-yl]carbamate( 370)

In a manner similar to general procedure 6, 2-(2-{[(tert-butoxy)carbonyl]amino}-2-methylpropyl)-1,3-thiazole-4-carboxylic acid (368) in DMF (6 ml). ) (0.28 g, 0.63 mmol, purity 68%), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (0.20 g, 1.01 mmol), HATU (0.4 g, 1. 04 mmol) and DIPEA (0.4 ml, 2.29 mmol) were stirred at room temperature for 2 hours and after purification by flash column chromatography (eluting with a gradient of 0-100% EtOAc/heptane) the title compound (0.33 g, 84 %, purity 72%) was obtained as a dark yellow oil. Used without further purification.

1H-NMR (DMSO-d6, 250MHz): d [ppm] = 8.58 (t, J = 5.6Hz, 1H), 8.39 (dt, J = 4.7, 1.5Hz, 1H), 8.19 (s, 1H), 7.78-7.63 (m, 1H), 7.47-7.35 (m, 1H), 6.68 (s, 1H), 4.67 (dd, J=5.6, 1.3 Hz, 2H), 3.41 (s, 2H), 1.41 (s, 9H), 1.23 (s, 6H)
HPLC MS (Method A): [m/z]: 409.05 [M+H] ^+.
tert-Butyl N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)-2-methylpropyl]carbamate (371)

In a similar manner to General Procedure 6, 2-(1-{[(tert-butoxy)carbonyl]amino}-2-methylpropan-2-yl)-1,3 in DCM (8 ml) for 17 hours at room temperature. -Thiazol-4-carboxylic acid (369) (0.64 g, 1.73 mmol, purity 83%), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (0.41 g, 2.08 mmol). , HATU (0.79 g, 2.08 mmol) and DIPEA (0.99 ml, 5.71 mmol) by flash column chromatography (eluting with a gradient of 0-100% EtOAc/heptane) after the title compound (1. (78 g, 90% purity) was obtained as a yellow oil which solidified on standing.

1H-NMR (DMSO-d6, 250MHz): d[ppm]=8.71(t, J=5.8Hz, 1H), 8.43-8.33(m, 1H), 8.15(s, 1H), 7.76-7.65 (m, 1H), 7.47-7.34 (m, 1H), 6.97 (t, J=6.3 Hz, 1H), 4.67 (dd, J=5.8, 1.5Hz, 2H), 3.25(d, J=6.5Hz, 2H), 1.34(s, 6H), 1.34(s, 9H)
HPLCMS (Method A): [m/z]: 409.45 [M+H] ^+.
2-(2-Amino-2-methylpropyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide dihydrochloride (372)

In a similar manner to General Procedure 2 tert-butyl N-[1-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1 in MeOH (5 ml) at 50° C. for 2 hours. ,3-thiazol-2-yl)-2-methylpropan-2-yl]carbamate (370) (0.33 g, 0.58 mmol, 72% purity) and 12M HCl (0.73 ml, 8.78 mmol). The title compound (0.26 g, 90%, purity 76%) was obtained as a beige residue which was used in the next step without purification.

1H-NMR (MeOD, 250 MHz): d[ppm]=8.53 (dd, J=5.3, 1.0 Hz, 1H), 8.24 (s, 1H), 8.16-8.06( m, 1H), 7.82-7.73 (m, 1H), 4.91 (d, J=1.4Hz, 2H), 3.42 (s, 2H), 1.46 (s, 6H).
HPLC MS (Method A): [m/z]: 308.95 [M+H] ⁺ as free base.
2-(1-Amino-2-methylpropan-2-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide dihydrochloride (373)

In a similar manner to general procedure 2 for 70 h at room temperature in tert-butyl N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1, MeOH (30 ml). 3-Thiazol-2-yl)-2-methylpropyl]carbamate (371) (1.78 g, 3.93 mmol, 90% purity) and 12M HCl (6.61 ml, 79.3 mmol) gave the title compound (1. 54 g, 98%) was obtained as a brown foam. Use without purification.

1H-NMR (MeOD, 250 MHz): d[ppm]=8.49-8.44 (m, 1H), 8.24 (s, 1H), 7.98-7.88 (m, 1H), 7 .68-7.59 (m, 1H), 4.88 (d, J=1.5Hz, 2H), 3.37 (s, 2H), 1.58 (s, 6H)
HPLC MS (Method A): [m/z]: 309.00 [M+H] ⁺ as free base.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]-2-methylpropyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3- Thiazole-4-carboxamide (Example compound 231)

In a manner similar to General Procedure 3, 2-(2-amino-2-methylpropyl)-N-[(3-fluoropyridin-2-yl)methyl in MeOH (5 ml) for 3.5 hours at 50°C. ]-1,3-Thiazole-4-carboxamide dihydrochloride (372) (0.26 g, 0.52 mmol, purity 77%), 1H-1,3-benzodiazol-2-carbaldehyde (0.106 g, 0.73 mmol), DIPEA (0.36 ml, 2.09 mmol) followed by NaBH ₄ (35 mg, 0.93 mmol) at 0° C. for kp-NH flash column chromatography (0-6% MeOH/0. After purification by elution with a gradient of DCM) followed by flash column chromatography (elution with a gradient of 0-20% MeOH/DCM), the title compound (0.054g, 24%) was obtained as a cream solid.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.14-8.12 (m, 1H), 8.11 (s, 1H), 7.52-7.46 (m, 1H), 7 .46-7.41 (m, 2H), 7.27-7.22 (m, 1H), 7.17-7.12 (m, 2H), 4.70 (d, J=1.5Hz, 2H), 4.21 (s, 2H), 3.27 (s, 2H), 1.25 (s, 6H)
HPLC MS (Method C): [m/z]: 439.1 [M+H] ^+.
2-(1-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}-2-methylpropan-2-yl)-N-[(3-fluoropyridine-2- Iyl)methyl]-1,3-thiazole-4-carboxamide (Example compound No. 242)

2-(1-Amino-2-methylpropan-2-yl)-N-[(3-fluoropyridin-2-yl) in MeCN (35 ml) in the same manner as general procedure 8 for 18 hours at room temperature. Methyl]-1,3-thiazole-4-carboxamide dihydrochloride (373) (1.54 g, 3.85 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (0.81 g, 4 .24 mmol) and DBU (1.73 ml, 11.56 mmol) afforded a mixture of monoalkylated:bisalkylated adduct (3.7:1) (2.23 g) as an orange oil. This was further reacted with iron powder (0.86g) in AcOH (10ml) at 75°C for 0.5h, flash column chromatography (eluting with a gradient of 0-40% MeOH/DCM) followed by kp-NH. After purification by column chromatography (eluting with a gradient of 0-5% MeOH/DCM) and basic preparative HPLC, the title compound (0.29 g, 17%) was obtained as an off-white solid.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.30-8.25 (m, 1H), 7.97 (s, 1H), 7.57-7.52 (m, 1H), 7 .43-7.35 (m, 2H), 7.34-7.29 (m, 1H), 7.18-7.13 (m, 2H), 4.65 (d, J=1.5Hz, 2H), 3.09-3.05 (m, 2H), 3.05-3.01 (m, 2H), 2.98 (s, 2H), 1.46 (s, 6H).
HPLC MS (Method C): [m/z]: 453.1 [M+H] ^+.
General scheme 1 above:
N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-methylpyridin-2-yl)methyl]carbamoyl}-1,3-thiazole-2 -Yl)ethyl]carbamate (441)

2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl in DMF (50 ml) in a similar manner to general procedure 6 for 16 hours. }-1,3-Thiazol-4-carboxylic acid (8) (2.75 g, 6.49 mmol), 1-(3-methylpyridin-2-yl)methanamine (1.19 g, 9.74 mmol), DIPEA( 3.39 ml, 19.47 mmol) and HATU (4.94 g, 12.98 mmol), purified by flash column chromatography (Kp-NH, eluting with a gradient of 20-100% EtOAc/heptane), followed by heptane. After azeotroping with, the title compound (1.7 g, 51%) was obtained as a yellow foam.

1H-NMR (MeOD, 250 MHz): d[ppm]=8.32 (d, J=4.4 Hz, 1H), 8.09 (s, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.53 (s, 2H), 7.30-7.14 (m, 3H), 4.74 (s, 2H), 4.69 (s, 2H), 3.86 (s, 2H). ), 3.34 (s, 3H), 2.40 (s, 3H), 1.40 (s, 10H)
HPLC MS (Method C): [m/z]: 507.1 [M+H] ^+.
2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-methylpyridin-2-yl)methyl]-1,3-thiazole-4- Carboxamide trihydrochloride (Example compound No. 55)

In a similar manner to General Procedure 2 for 16 hours at room temperature in tert-butyl N-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{ in dioxane (30 ml). [(3-Methylpyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (441) (1.7 g, 3.36 mmol) and 4M HCl/dioxane (8.4 ml). ) From Et ₂ O (2×30 ml), DCM (2×20 ml) and Et ₂ O (2×30 ml) followed by recrystallisation from DCM/MeOH and heptane. 1.09 g, 63%) was obtained as a white solid.

1H-NMR (DMSO-d6, 500MHz): d [ppm] = 10.29 (s, 1H), 9.56 (t, J = 5.6Hz, 1H), 8.64-8.57 (m, 1H), 8.37(d, J=7.7Hz, 1H), 8.29(s, 1H), 7.85(dd, J=7.8, 5.8Hz, 1H), 7.73( dt, J=6.6, 3.3 Hz, 2H), 7.41 (dt, J=6.1, 3.3 Hz, 2H), 4.85 (d, J=5.7 Hz, 3H), 4 .74 (s, 2H), 3.64 (dt, J=35.5, 7.0 Hz, 5H), 2.50 (s, 3H)
HPLC MS (method C): [m/z]: 407.05 [M+H] ^+.
General Scheme 41 above:
tert-Butyl 3-[(pyridin-2-ylmethyl)carbamoyl]-4H,5H,6H,7H-thieno[2,3-c]pyridine-6-carboxylate (449)

In a similar manner to general procedure 6 for 6 hours at room temperature in DCM (12 ml) 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- Flash column chromatography with carboxylic acid (220 mg, 0.77 mmol), 1-(pyridin-2-yl)methanamine (88 μl, 0.85 mmol), DIPEA (407 μl, 2.33 mmol) and HATU (443 mg, 1.17 mmol). The title compound (466 mg) was obtained as a yellow oil after purification by chromatography (eluting with gradient 50-100% EtOAc/heptane).

_{1H-NMR (CDCl 3, 500MHz} ): d [ppm] = 8.55 (d, J = 4.8Hz, 1H), 7.68 (td, J = 7.7,1.8Hz, 1H), 7 .64 (s, 1H), 7.31 (d, J=7.8Hz, 1H), 7.22 (dd, J=7.2, 5.2Hz, 1H), 4.70 (d, J= 4.8 Hz, 2H), 4.62 (s, 2H), 3.76-3.61 (m, 2H), 2.99 (s, 2H), 1.48 (s, 9H), 1.44. (D, J=6.6Hz, 1H)
HPLC MS (Method E): [m/z]: 374.05 [M+H] ^+.
N-(pyridin-2-ylmethyl)-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide (450)

In a similar manner to General Procedure 2 for 16 h at room temperature in tert-butyl 3-[(pyridin-2-ylmethyl)carbamoyl]-4H,5H,6H,7H-thieno[2,3-] in DCM (5 ml) c] Pyridine-6-carboxylate (449) (466 mg, 1.09 mmol) and TFA (940 μl) gave the title compound (130 mg, 44%) as a yellow oil. The compound was used in the next step without purification.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.49 (d, J=4.3 Hz, 1H), 7.92 (s, 1H), 7.82 (td, J=7.7, 1.8 Hz, 1 H), 7.43 (d, J=7.9 Hz, 1 H), 7.37-7.27 (m, 1 H), 4.59 (s, 2 H), 4.16 (s, 2H), 3.21 (t, J=6.0 Hz, 2H), 3.01 (t, J=6.0 Hz, 2H)
HPLC MS (Method E): [m/z]: 273.95 [M+H] ^+.
6-(1H-1,3-benzodiazol-2-ylmethyl)-N-(pyridin-2-ylmethyl)-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide( Example compound No. 48)

In a manner similar to general procedure 7 for 72 hours at room temperature in N-(pyridin-2-ylmethyl)-4H,5H,6H,7H-thieno[2,3-c]pyridine-3- in acetone (3 ml). carboxamide _{(450) (65mg, 0.24mmol)} , K 2 CO 3 (49mg, 0.36mmol) and 2-by (chloromethyl)-1H-benzimidazole (44 mg, 0.26 mmol), flash column chromatography (kp -NH, eluting with a gradient of 0-10% MeOH/DCM), followed by purification by basic preparative HPLC to give the title compound (25 mg, 26%) as a pale yellow solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.36 (s, 1H), 8.78 (t, J=6.0 Hz, 1H), 8.50 (d, J=4. 7 Hz, 1 H), 7.95 (s, 1 H), 7.76 (td, J=7.7, 1.7 Hz, 1 H), 7.49 (s, 2 H), 7.31 (d, J= 7.8 Hz, 1 H), 7.29-7.23 (m, 1 H), 7.14 (dd, J=5.9, 3.1 Hz, 2 H), 4.49 (d, J=6.0 Hz). , 2H), 3.93 (s, 2H), 3.73 (s, 2H), 2.89 (d, J=5.5 Hz, 2H), 2.79 (t, J=5.7 Hz, 2H). )
HPLCMS (Method D): [m/z]: 404.2 [M+H] ^+.
6-[2-(1H-1,3-benzodiazol-2-yl)ethyl]-N-(pyridin-2-ylmethyl)-4H,5H,6H,7H-thieno[2,3-c]pyridine -3-carboxamide (Example compound No. 49)

In a similar manner to general procedure 7 for 24 hours at room temperature in N-(pyridin-2-ylmethyl)-4H,5H,6H,7H-thieno[2,3-c]pyridine-3- in acetone (3 ml). carboxamide _{(450) (65mg, 0.24mmol)} , K 2 CO 3 (49mg, 0.36mmol) and 2- (2-chloroethyl)-1H-benzimidazole (47 mg, 0.26 mmol), followed by DMF (5 ml) , NaI (39 mg, 0.26 mmol), DIPEA (0.16 ml, 0.95 mmol) and 2-(2-chloroethyl)-1H-benzimidazole (94 mg, 0.52 mmol) at room temperature for 72 hours. After purification by basic preparative HPLC, the title compound (9 mg, 9%) was obtained as an orange solid.

1H-NMR (DMSO-d6,500MHz): d[ppm]=12.17(s, 1H), 8.75(t, J=6.0Hz, 1H), 8.50(d, J=4. 2Hz, 1H), 7.94(s, 1H), 7.75(td, J=7.7, 1.8Hz, 1H), 7.46(s, 2H), 7.31(d, J= 7.8 Hz, 1 H), 7.28-7.23 (m, 1 H), 7.10 (dd, J=6.0, 3.1 Hz, 2 H), 4.48 (d, J=6.0 Hz). , 2H), 3.71 (s, 2H), 3.05 (t, J=7.2 Hz, 2H), 2.96 (t, J=7.2 Hz, 2H), 2.82 (d, J). =5.3 Hz, 2H), 2.75 (t, J=5.7 Hz, 2H)
HPLCMS (Method B): [m/z]: 418.2 [M+H] ^+.
General scheme 42 above:
2-{2-[N-(1H-1,3-benzodiazol-2-ylmethyl)-2-bromoacetamido]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1, 3-thiazole-4-carboxamide (451)

2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4- Carboxamide (Example Compound No. 40) (150 mg, 0.37 mmol) and TEA (127 μl, 0.91 mmol) were dissolved in DCM (10 ml), and bromoacetyl chloride (61 μl, 0.73 mmol) was added dropwise. The mixture was stirred at room temperature for 15 minutes, then quenched with saturated NaHCO ₃ (aq) (20 ml) and extracted with DCM (3×30 ml) and 4:1 chloroform/IPA (30 ml). The combined organic extracts were dried (Na ₂ SO ₄ ) and evaporated in vacuo. Purification by flash column chromatography (eluting with a gradient of 0-5% MeOH/DCM) provided the title compound (224 mg, 82% pure) as a brown residue. The compound was used in the next step without further purification.

HPLC MS (Method M): [m/z]: 530.85/532.85 [M+H] ^+.
N-[(3-fluoropyridin-2-yl)methyl]-2-(2-{12-oxo-1,8,11-triazatricyclo[7.4.0.0 ^2,7 ]trideca- 2(7),3,5,8-Tetraen-11-yl}ethyl)-1,3-thiazole-4-carboxamide (Example compound No. 275)

2-{2-[N-(1H-1,3-benzodiazol-2-ylmethyl)-2-bromoacetamido]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1, 3-Thiazole-4-carboxamide (451) (220 mg, 0.41 mmol, 82% purity) was dissolved in THF (10 ml) and NaH (60%, 50 mg, 1.24 mmol) was added. The mixture was stirred at room temperature for 10 minutes. The reaction was quenched with saturated NaHCO ₃ (aq) (20 ml) and extracted with DCM (3×20 ml) and 4:1 chloroform/IPA (20 ml). The combined organic extracts were dried (Na ₂ SO ₄ ) and evaporated in vacuo. Purification by basic preparative HPLC gave the title compound (15 mg, 8%) as an off-white solid.

1H-NMR (DMSO-d6, 500MHz): d[ppm]=8.65(t, J=5.6Hz, 1H), 8.36-8.32(m, 1H), 8.18(s, 1H), 7.71-7.64 (m, 1H), 7.61 (dt, J=5.4, 3.4Hz, 1H), 7.56-7.51 (m, 1H), 7. 40-7.34 (m, 1H), 7.26-7.21 (m, 2H), 4.91 (s, 2H), 4.88 (s, 2H), 4.63-4.57( m, 2H), 3.93 (t, J=7.2 Hz, 2H), 3.42 (t, J=7.2 Hz, 2H)
HPLCMS (Method B): [m/z]: 451.2 [M+H] ^+.
N - [(3- fluoropyridin-2-yl) methyl] -2- (2- {1,8,11- triazatricyclo [7.4.0.0 ^{2, 7]} trideca-2 (7) ,3,5,8-Tetraen-11-yl}ethyl)-1,3-thiazole-4-carboxamide (Example compound No. 276)

2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4- Carboxamide (Example Compound No. 40) (150 mg, 0.37 mmol) and TEA (509 μl, 3.65 mmol) were combined in DMF (4 ml) and 1,2-dibromoethane (315 μl, 3.65 mmol) was added. The mixture was heated at 100° C. for 40 minutes, then cooled to room temperature and quenched with saturated NaHCO ₃ (aq). The mixture was extracted with DCM (3×50 ml), the combined organic extracts were washed with aqueous LiCl solution (2M, 50 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo. Purification by basic preparative HPLC, followed by flash column chromatography (gradient 0-4% eluting with MeOH/DCM) afforded the title compound (45 mg, 28%) as a pale yellow solid.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.37 (dt, J=4.7, 1.2 Hz, 1H), 8.09 (s, 1H), 7.64-7.57( m, 2H), 7.51-7.46 (m, 1H), 7.42-7.37 (m, 1H), 7.32-7.26 (m, 2H), 4.80 (d, J=1.6Hz, 2H), 4.23(t, J=5.5Hz, 2H), 4.04(s, 2H), 3.41(t, J=6.8Hz, 2H), 3. 25-3.20 (m, 2H), 3.16 (t, J=6.8Hz, 2H)
HPLCMS (Method B): [m/z]: 437.1 [M+H] ^+.
tert-Butyl (2-(4-(((3-fluoropyridin-2-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)ethyl)carbamate (452)

1-(2-((tert-Butoxycarbonyl)amino)ethyl)-1H-1,2,3-triazole-4-carboxylic acid (commercially available) (2.0 g, 7.8 mmol) in 50 ml DCM to -5°C. Upon cooling, N-methylmorpholine (0.94 ml, 8.6 mmol) and ethyl chloroformate were added to the mixture. The temperature was kept below 0° C. during the addition and after addition the mixture was stirred at 0° C. for 1 hour. A second portion of N-methylmorpholine (2.7 ml, 24.2 mmol) and (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) were added. The reaction was warmed to room temperature and stirred overnight. 50 ml of water was added to the reaction and extracted with DCM. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to give the crude product which was purified by flash column chromatography to give the title compound (2.1 g, 74%).

1H-NMR (DMSO, 400 MHz): d[ppm]=8.82 (t, 1H), 8.50 (s, 1H), 8.38 (d, 1H), 7.70 (m, 1H), 7.40 (m, 1H), 7.01 (s, 1H), 4.65 (d, 2H), 4.46 (m, 2H), 3.39 (m, 2H), 1.40-1 .24 (m, 9H)
1-(2-aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride (453)

16 ml of concentrated HCl was added to tert-butyl(2-(4-(((3-fluoropyridin-2-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)ethyl)carbamate (452 ) (2.00 g, 5.49 mmol) in 100 ml of methanol was added, and the mixture was stirred at room temperature for 2 hours. The mixture was evaporated in vacuo to give the title compound (1.74g, 99%) as a white solid.

1H-NMR (DMSO, 400 MHz): d[ppm]=8.99 (t, 1H), 8.73 (s, 1H), 8.51 (s, 3H), 8.45 (d, 1H), 7.87 (m, 1H), 7.53 (m, 1H), 4.78 (m, 2H), 4.71 (d, 2H), 3.37 (m, 2H)
N-((3-fluoropyridin-2-yl)methyl)-1-(2-((3-((2-nitrophenyl)amino)-3-oxopropyl)amino)ethyl)-1H-1,2 , 3-triazole-4-carboxamide (454)

1-(2-aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride (453) (4.46 g, 13. 2 mmol) and DBU (10.1 g, 66.1 mmol) were suspended in 120 ml of acetonitrile. N-(2-Nitrophenyl)prop-2-enamide (D) (2.54 g, 13.2 mmol) in 10 ml of acetonitrile was added dropwise to the reaction mixture within 1 hour and stirred at room temperature overnight. The reaction was evaporated to dryness and redissolved in 100 ml DCM. 50 ml of water was added and extracted with DCM. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the crude product which was purified by flash column chromatography to give the title compound (2.1 g, 35%). Was given.

1H-NMR (DMSO, 400 MHz): d [ppm] = 10.55 (s, 1H), 8.78 (t, 1H), 8.57 (s, 1H), 8.38 (d, 1H), 7.93 (m, 1H), 7.76-7.62 (m, 3H), 7.40 (m, 1H), 7.32 (m, 1H), 4.65 (d, 2H), 4 .50 (m, 2H), 3.02 (t, 2H), 2.81 (t, 2H), 2.51 (m, 2H)
1-(2-((2-(1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)-1H-1,2 ,3-triazole-4-carboxamide (Example compound No. 277)

N-((3-fluoropyridin-2-yl)methyl)-1-(2-((3-((2-nitrophenyl)amino)-3-oxopropyl)amino)ethyl)-1H-1,2 , 3-Triazole-4-carboxamide (454) (900 mg, 1.97 mmol) and iron powder (335 mg, 5.92 mmol) were suspended in 10 ml of acetic acid and stirred under nitrogen at 80°C for 2 hours. The reaction mixture was evaporated to dryness and the residue was treated with 60 ml of chloroform/isopropanol (1:4). The pH was adjusted to 11 by the addition of 1N NaOH and the phases were separated. After extraction of the aqueous phase with chloroform, the combined organic phases were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the crude product, which was purified by flash column chromatography to give the title: The compound (430 mg, 53%) was obtained.

1H-NMR (d4-methanol, 400 MHz): d[ppm]=8.40 (s, 1H), 8.38 (m, 1H), 7.63-7.58 (m, 1H), 7.50. -7.45 (m, 2H), 7.41-7.36 (m, 1H), 7.18-12 (m, 2H), 4.78 (d, 2H), 4.56 (m, 2H) ), 3.16 (t, 2H), 3.10-3.0 (m, 4H)
5-(2-((tert-Butoxycarbonyl)amino)ethyl)-1,2,4-oxadiazole-3-carboxylic acid

Ethyl 5-(2-((tert-butoxycarbonyl)amino)ethyl)-1,2,4-oxadiazole-3-carboxylate (4 g, 14.06 mmol), THF (80 ml) and water in a round bottom flask. (20 ml) was added at room temperature with stirring. Lithium hydroxide (1 g, 41.75 mmol) was then added to the solution and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then acidified to pH 2.8 (using 32% aq. HCl), extracted with ethyl acetate (3×80 ml), dried (Na 2 SO 4 ), filtered and evaporated to give the title compound as a brown oil. Obtained as (2.95 g) and used without purification.

tert-butyl (2-(3-((pyridin-2-ylmethyl)carbamoyl)-1,3,4-oxadiazol-5-yl)ethyl)carbamate

To a solution of 5-(2-((tert-butoxycarbonyl)amino)ethyl)-1,2,4-oxadiazole-3-carboxylic acid (2.95 g, 11.47 mmol) in 100 ml of dichloromethane at 0°C was added, 4-Methylmorpholine (2.8 ml, 25.47 mmol) and ethyl chloroformate (1 ml, 10.46 mmol) were added. After stirring at 0° C. for 60 minutes, 2-picolylamine (1.7 ml, 16.82) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water (100 ml), dried (Na2SO4), filtered and evaporated. The crude product was purified using a 100 g SNAP Ultra column (eluting with a gradient of 0-100% ethyl acetate in petroleum ether) to give a light brown oil (2.29 g, 6.6 mmol, 58%).

¹ H NMR (400 MHz, CDCl3): δ 8.5 (s, 1H), 8.1 (m, 2H), 7.7 (m, 1H), 7.3 (m, 2H), 6.8 ( s, 1H), 4.6 (s, 2H), 3.4 (m, 2H), 2.5 (m, 2H), 1.4 (s, 9H).
5-(2-aminoethyl)-N-(pyridin-2-ylmethyl)-1,2,4-oxadiazole-3-carboxamide dihydrochloride

tert-Butyl (2-(3-((pyridin-2-ylmethyl)carbamoyl)-1,2,4-oxadiazol-5-yl)ethyl)carbamate (2.41 g, 6.94 mmol) in dioxane (25 ml) 4M HCl in dioxane (25 ml) was added to the solution in ). After stirring for 2 hours at room temperature, the reaction mixture was evaporated to give the title compound as a brown oil (2.83 g), which was used without purification.

5-(2-((3-((2-nitrophenyl)amino)-3-oxopropyl)amino)ethyl)-N-(pyridin-2-ylmethyl)-1,2,4-oxadiazole-3 -Carboxamide

In a round bottom flask, 5-(2-aminoethyl)-N-(pyridin-2-ylmethyl)-1,2,4-oxadiazole-3-carboxamide dihydrochloride (3.48 g, 9.76 mmol). Was suspended in acetonitrile (100 ml) under nitrogen and 1,8-diazabicycloundec-7-ene (DBU) (7.1 ml, 47.48 mmol, 4.9 eq) followed by N-(2- Nitrophenyl)prop-2-enamide (1.9 g, 9.89) was added dropwise. The reaction was stirred at room temperature overnight, then evaporated, diluted with 100 ml dichloromethane, washed with 50 ml water, dried (Na ₂ SO ₄ ), filtered and evaporated. The crude product was purified using a 100 g SNAP Ultra column (eluting with a gradient of 0-25% methanol in dichloromethane each time) to give a light brown oil (0.74 g, 1.7 mmol, 17%).

¹ H NMR (400 MHz, CDCl3): δ 8.5 (s, 1H), 8.1 (m, 2H), 7.8 (m, 1H), 7.6 (m, 1H), 7.3 ( m, 3H), 4.4 (s, 2H), 3.1 (m, 4H), 2.7 (m, 2H), 2.5 (m, 2H).
5-(2-((2-(1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-(pyridin-2-ylmethyl)-1,2,4-oxadiazole-3 -Carboxamide (Example compound 278)

5-(2-((3-((2-nitrophenyl)amino)-3-oxopropyl)amino)ethyl)-N-(pyridin-2-ylmethyl)-1,2,4-oxadiazole-3 -Carboxamide (0.74 g, 1.68 mmol) was dissolved in acetic acid (5 ml) under nitrogen and iron powder (0.3 g) was added. The reaction mixture was heated to 80° C. for 3 hours. After cooling at room temperature, toluene (50 ml) was added and the mixture was evaporated. A mixture of chloroform:IPA (4:1, 40 ml) was added, the reaction mixture was cooled to 0° C., basified to pH 10-12 with 6M NaOH solution, filtered and dried (Na ₂ SO ₄ ). Filtered and evaporated. The crude product was purified using a 50 g SNAP KP-Sil column (eluted with a gradient of 0-25% methanol in dichloromethane) to give a light brown oil (0.31 g, 0.8 mmol, 47%).

¹ H NMR (400 MHz, MeOD): δ 8.4 (s, 1 H), 7.9 (s, 1 H), 7.7 (m, 2 H), 7.3 (m, 1 H), 7.2 ( m, 1H), 7.1 (m, 2H), 4.4 (s, 2H), 3.1 (m, 4H), 2.9 (m, 2H), 2.5 (m, 2H).
tert-Butyl (2-(3-(((3-fluoropyridin-2-yl)methyl)carbamoyl)-1,2,4-oxadiazol-5-yl)ethyl)carbamate

To a solution of 5-(2-((tert-butoxycarbonyl)amino)ethyl)-1,2,4-oxadiazole-3-carboxylic acid (8.16 g, 31.72 mmol) in 400 ml of dichloromethane at -5°C. , 4-Methylmorpholine (20 ml, 182 mmol) and ethyl chloroformate (2.7 ml, 28.24 mmol) were added. After stirring at -5°C for 60 minutes, (3-fluoropyridin-2-yl)methanamine dihydrochloride (9.50, 47.73) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water (400 ml), dried (Na2SO4), filtered and evaporated. The crude product was purified using a 100 g SNAP Ultra column (eluted with a gradient of 0-100% ethyl acetate in petroleum ether) to give a light brown oil (4.15 g, 11.4 mmol, 36%).

¹ H NMR (400 MHz, CDCl3): δ 8.3 (s, 1H), 7.4 (m, 1H), 7.3 (m, 1H), 6.9 (s, 1H), 4.6 ( s, 2H), 3.4 (m, 2H), 2.5 (m, 2H), 1.4 (s, 9H).
5-(2-aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)-1,2,4-oxadiazole-3-carboxamide dihydrochloride

tert-Butyl (2-(3-(((3-fluoropyridin-2-yl)methyl)carbamoyl)-1,2,4-oxadiazol-5-yl)ethyl)carbamate (4.23 g, 11. To a solution of 58 mmol) in dioxane (50 ml) was added 4M HCl in dioxane (50 ml). After stirring for 3 hours at room temperature, the reaction mixture was evaporated to give the title compound as a brown oil (3.78 g) which was used without purification.

N-((3-fluoropyridin-2-yl)methyl)-5-(2-((3-((2-nitrophenyl)amino)-3-oxopropyl)amino)ethyl)-1,2,4 -Oxadiazole-3-carboxamide

In a round bottom flask, 5-(2-aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)-1,2,4-oxadiazole-3-carboxamide dihydrochloride (3. 72 g, 9.93 mmol) were suspended in acetonitrile (100 ml) under nitrogen and 1,8-diazabicycloundec-7-ene (DBU) (7.42 ml, 49.65 mmol, 5 eq) followed by N 2. -(2-Nitrophenyl)prop-2-enamide (1.91 g, 9.93) was added dropwise. The reaction was stirred at room temperature overnight, then evaporated, diluted with 100 ml dichloromethane, washed with 50 ml water, dried (Na ₂ SO ₄ ), filtered and evaporated. The crude product was purified using a 100 g SNAP KP-Sil column (eluted with a gradient of 0-25% methanol in dichloromethane) to give a light brown oil (1.7 g, 3.7 mmol, 37%).

¹ H NMR (400 MHz, MeOD): δ 8.3 (s, 1 H), 8.1 (m, 2 H), 7.6 (m, 1 H), 7.5 (m, 1 H), 7.3 ( m, 2H), 4.5 (s, 2H), 3.0 (m, 4H), 2.7 (m, 2H), 2.5 (m, 2H).
5-(2-((2-(1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)-1,2,4 -Oxadiazole-3-carboxamide (Example compound 279)

N-((3-fluoropyridin-2-yl)methyl)-5-(2-((3-((2-nitrophenyl)amino)-3-oxopropyl)amino)ethyl)-1,2,4 -Oxadiazole-3-carboxamide (2.3 g, 5.03 mmol) was dissolved in acetic acid (20 ml) under nitrogen and iron powder (1.4 g) was added. The reaction mixture was heated to 80° C. for 3 hours. After cooling at room temperature, toluene (200 ml) was added and the mixture was evaporated. A mixture of chloroform:IPA (4:1, 100 ml) was added, the reaction mixture was cooled to 0° C., basified to pH 10-12 with 6M NaOH solution, filtered and dried (Na ₂ SO ₄ ). Filtered and evaporated. The crude product was purified using a 100 g SNAP KP-Sil column (eluted with a gradient of 0-25% methanol in dichloromethane) to give a light brown oil (1.51 g, 3.7 mmol, 74%).

¹ H NMR (400 MHz, MeOD): δ 8.2 (s, 1 H), 7.5 (m, 3 H), 7.3 (m, 1 H), 7.1 (m, 2 H), 4.5 ( s, 2H), 3.1 (m, 4H), 2.9 (m, 2H), 2.4 (m, 2H).
2-(1-((1H-benzo[d]imidazol-2-yl)methyl)azetidin-3-yl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-5-carboxamide (implementation (Example compound No. 280)

In a round bottom flask, 2-(azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-5-carboxamide dihydrochloride (Example compound above) The same starting compound as in the preparation of No. 2) (4 g, 11.5 mmol) was diluted in dichloromethane (1600 ml) under nitrogen and diisopropylethylamine (20 ml, 115 mmol, 11 eq) was added dropwise. The reaction was stirred at room temperature for 10 minutes, then 1H-benzo[d]imidazol-2-carbaldehyde (2 g, 13.7 mmol, 1.3 eq) was added. The reaction was stirred at room temperature for 18 hours, then sodium triacetoxyborohydride (5 g, 23.6 mmol, 2.3 eq) was added and the reaction was stirred at room temperature for 18 hours. The reaction mixture was washed with water (1000 ml), separated, dried (MgSO4), filtered and evaporated. The crude product was purified using a 100 g SNAP Ultra column, then a 55 g SNAP NH column (eluting with a gradient of 0-25% methanol in dichloromethane respectively) to give a light brown oil (1.34 g, 3.3 mmol, 29%). Was obtained.

¹ H NMR (400 MHz, CDCl 3): δ 7.99 (m, 1 H), 7.51 (m, 1 H), 7.15 (m, 2 H), 7.01 (m, 1 H), 6.88 ( m, 1H), 6.81 (m, 2H), 4.4 (s, 2H), 3.6 (2H), 3.42 (m, 1H), 3.35 (m, 2H), 3. 28 (m, 2H).
MS (ESI+): m/z 407 [M+H] ^< +>.

Further embodiments of the invention:
1. Compound according to formula (I)

(In the formula,
R ¹ and R ² are the same or different,
-Hydrogen,
-Optionally substituted alkyl,
-Optionally substituted aryl,
-Independently selected from the group consisting of optionally substituted heteroaryl, or-R< ¹ > and R< ² >, together with the nitrogen atom to which they are attached, may contain further heteroatoms. A good, optionally substituted 3- to 6-membered ring is formed;
X is O or S;
Y is hydrogen, optionally substituted alkyl or halogen,
A ¹ is -optionally substituted alkanediyl;
A ² is an optionally substituted alkanediyl,
A direct bond or a sulfonyl group;
R ³ is —hydrogen, or —optionally substituted alkyl; or A ¹ and R ³ together with the nitrogen atom to which they are attached are optionally substituted 4 to 6 members. A membered aliphatic monocyclic or bicyclic ring; or R ³ and A ² together with the nitrogen atom to which they are attached are optionally substituted 4-7 membered aliphatic Form a ring;
Ar is-an optionally substituted aryl,
-Optionally substituted monocyclic heteroaryl, or -substituent which, together with the nitrogen atom to which R ³ and A ² are attached, can be fused with the ring formed by R ³ and A ² . Which is optionally bicyclic heteroaryl)
Or a pharmaceutically acceptable salt thereof.

2. R ¹ and R ² are the same or different,
-Hydrogen,
-Optionally substituted alkyl,
Independently selected from the group consisting of, or —R ¹ and R ² together with the nitrogen atom to which they are attached may contain further heteroatoms, optionally substituted 3 Form a 6-membered ring;
X is O or S;
Y is hydrogen or C ₁ -C ₃ -alkyl, eg preferably hydrogen or methyl;
A ¹ is an optionally substituted alkanediyl;
A ² is-an optionally substituted alkanediyl, or-a direct bond;
R ³ is -hydrogen, or -C ₁ -C ₃ -alkyl; or A ¹ and R ³ together with the nitrogen atom to which they are attached are optionally substituted 4-membered aliphatic Form a monocyclic ring; or R ³ and A ² together with the nitrogen atom to which they are attached form an optionally substituted 4-7 membered aliphatic ring;
Ar is an optionally substituted bicyclic heteroaryl,
The compound according to embodiment 1.

3. At least one of R ¹ and R ² is a compound according to formula (III)

A linear, branched or cyclic alkyl group substituted with a cyclic group "Cycl" called R2 ^* , which forms
Cycl is selected from -optionally substituted aryl, and -optionally substituted heteroaryl,
n is an integer of 1 to 3;
The remainder of R ¹ or R ² referred to as R ^{1 *} is selected from —hydrogen, and —optionally substituted alkyl,
X, Y, R ³ , A ¹ , A ² and Ar have the meanings defined in embodiment 1 or 2.
The compound according to Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof.

4. -Formula (IIIa)

,
Or-formula (IIIb)

(Het-1 contains 1 or 2 identical or different heteroatoms selected from the group consisting of N, O and S, preferably N,
-Optionally substituted, optionally fused 5- or 6-membered heteroaryl, or-optionally substituted 5- or 6-membered aliphatic heterocyclyl, preferably 6-membered aliphatic heterocyclyl,
In each case n is an integer from 1 to 3;
The remainder of R ¹ or R ² , called R ^{1 *} , is
-Hydrogen, and-optionally substituted alkyl;
X, Y, R ³ , A ¹ , A ² and Ar have the meanings defined in Embodiments 1 to 3.)
A compound according to any one of embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, as defined by:

5. -Formula (IIIb-c)

,
-Formula (IIIb-d)

,
And-formula (IIIb-e)

(Wherein the pyrimidinyl, pyridazinyl and pyridinyl rings may each have 1 to 3, preferably 1 or 2 further substituents,
In each case n is an integer from 1 to 3;
The remainder of R ¹ or R ² , called R ^{1 *} , is
-Hydrogen, and-optionally substituted alkyl;
X, Y, R ³ , A ¹ , A ² and Ar have the meanings defined in Embodiments 1 to 4)
A compound according to any one of embodiments 1 to 4 or a pharmaceutically acceptable salt thereof, as defined by:

6. -Formula (IIIb-f)

Wherein R ⁵ represents an optional substituent selected from ₁ to ₃ , preferably 1 or 2, preferably C ₁ -C ₃ -alkyl and halogen, such as especially the formula: IIIb-g)

Where R ⁵ is preferably selected from C ₁ -C ₃ -alkyl and halogen, eg preferably F;
In each case n is an integer from 1 to 3;
The remainder of R ¹ or R ² , called R ^{1 *} , is
-Hydrogen, and-optionally substituted alkyl;
X, Y, R ³ , A ¹ , A ² and Ar have the meanings defined in Embodiments 1 to 5)
The compound according to any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, defined by the compound of

7. Ar is of formula (IV)

An optionally substituted monocyclic or bicyclic heteroaryl forming a compound according to
Het-2 is formed by R ³ and A ² together with the optionally substituted 5- or 6-membered monocyclic heteroaryl, or —R ³ and A ² to which the nitrogen atom is attached. An optionally substituted bicyclic heteroaryl capable of being condensed with a ring
X, Y, R ³ , A ¹ , A ² and Ar have the meaning defined in any one of Embodiments 1 to 6,
A compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 6.

8. -Formula (IVc)

(- both ^{Y 2} is C, or - one of ^{Y 2} is N, 1 single ^{Y 2} is C),
For example, especially a compound according to formula (IVd)

(Wherein the bicyclic heteroaryl ring of Het-2 may in each case have 1 to 3 substituents, preferably 1 or 2 substituents; formula (IVc) or The bicyclic heteroaryl ring of Het-2 of (IVd) may be fused with the ring atom formed by R ³ and A ² together with the nitrogen atom to which R ³ and A ² are attached. You can
(In each case R ¹ , R ² , X, Y, R ³ , A ¹ and A ² have the meanings defined in embodiments 1 to 7)
A compound according to any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, as defined by:

9. A ¹ and A ² are optionally substituted alkanediyl and are the same or different and are independently selected from -methylene and -ethane-1,2-diyl, or -A ¹ and R ³ together with the nitrogen atom to which they are attached form an optionally substituted 4-membered aliphatic monocyclic ring,
A compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 8.

10. A compound according to any one of embodiments 1 to 9 for use as a medicament.

11. A compound according to any one of embodiments 1 to 10 for use as a ferroportin inhibitor.

12. For use in the inhibition of iron transport mediated by ferroportin or for elevated iron levels, impaired iron metabolism leading to iron overload, diseases associated with or caused by elevated iron levels or tissue iron overload, ineffective erythropoiesis For use in the prevention and/or treatment of associated diseases, diseases caused by reduced hepcidin levels, or for limiting the amount of iron available to pathogenic microorganisms, such as the bacterium Vibrio vulnificus, and A compound according to any one of embodiments 1 to 11, for use as an adjunctive therapy thereby for treating an infection.

13. Diseases associated with or caused by elevated iron levels or iron overload include thalassemia (β-thalassemia), hemochromatosis, neurodegenerative diseases (such as Alzheimer's and Parkinson's disease), radicals, reactive oxygen species (ROS) and oxidation. Includes formation of stress, heart, liver and endocrine damage caused by iron overload, and inflammation induced by excess iron; diseases with ineffective erythropoiesis are myelodysplastic syndrome (MDS, myelodysplasia), polymorphism A compound according to any one of embodiments 1 to 12, for use according to embodiment 12, which comprises blood serum.

14. Preferably for use according to embodiments 12 and 13, one or more pharmaceutical carriers and/or auxiliaries and/or solvents and/or at least one further pharmaceutically active compound, in particular A compound for preventing and treating iron overload, thalassemia, hemochromatosis, neurodegenerative diseases (such as Alzheimer's disease or Parkinson's disease) and related conditions, preferably an iron chelate compound may be further included; preferably oral or parenteral A medicament comprising one or more of the compounds according to any one of embodiments 1 to 13, which is for administration.

Claims (23)

Compound according to formula (A-II)

(In the formula,
m is 0, 1, 2 or 3;
R ⁴ is
-Halogen,
-Cyano,
-Optionally substituted alkyl,
- optionally substituted alkoxy, and - indicates location substituent that could be selected from the group consisting of carboxyl group independently;
X ¹ is C, N, S or O;
X ² is C or N;
X ³ is C, N, S or O;
X ⁴ is C, N or S,
However, there are 1 to 3 heteroatoms X,
X ¹ , X ³ and X ⁴ when having the meaning of C or N may have further substituents;
R ¹ is selected from the group consisting of —hydrogen and —optionally substituted alkyl;
Cycl is selected from the group consisting of -substituted aryl and -substituted or unsubstituted heteroaryl;
Q is - may be formed hydrogen or -Cycl fused 5-membered or 6-membered ring _C 1 -C ₄ - alkyl;
n is Ri integer der of 0 or 1-8;
A ¹ is -unsubstituted linear or branched C ₁ -C ₄ -alkanediyl;
A ² is a straight-chain or branched C ₁ -C ₄ -alkanediyl which may be substituted with 1 or 2 substituents selected from halogen, hydroxy, oxo group and amino group, or —direct bond. ;
R ³ is - hydrogen, or - substituted is also alkyl; or A ¹ and R ^3, together with the nitrogen atom to which they are attached, 4-6 membered optionally substituted Forming a monocyclic or bicyclic ring; or R ³ and A ² together with the nitrogen atom to which they are attached form an optionally substituted 4 to 7 membered ring)
Or a pharmaceutically acceptable salt thereof. Cycl has the formula (A-IIIb)

Or formula (A-IVb)

By the compound (wherein
j is 0, 1, 2, 3 or 4;
R ⁵ is
-F and Cl,
- methyltransferase, trifluoromethyl, hydroxymethyl,
-Hydroxy,
- main butoxy,
-Expression

An oxo group (=O) forming a substituted pyridinyl group of
− -NH _2, mono - and amino groups are selected from dialkylamino - an amino group _{N H 2 - (C = O} ) -,
-Cyano, and
- motor Ruhoriniru showing the location substituent that could be independently selected from the group consisting group)
A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a substituted or unsubstituted pyridinyl which forms Formula (A-IVd)

The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, which comprises: R ⁵ is halogen, a compound or a pharmaceutically acceptable salt thereof according to any one of claims 2 or 3. C YCl A compound according to formula (A-Vb)

(In the formula,
p is 1, 2 or 3,
R ⁶ is
-Hydroxy,
-F or Cl,
-Cyano,
-Optionally substituted alkyl,
- _(-NH 2), mono- - and amino optionally substituted selected from dialkylamino,
-An optionally substituted acyl,
- main butoxy, di - fluoromethoxy and trifluoromethoxy,
-Optionally substituted aryloxy,
-Optionally substituted heterocyclyloxy,
-An optionally substituted aryl, and
- replacement which may pylori sulfonyl also be, morpholinyl and piperazinyl, and
-Expression

Represents a substituent independently selected from the group consisting of heterocyclyl-substituted sulfonyl)
The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is a substituted phenyl group that forms X ¹ is N,
There is one or two additional heteroatoms X (X ² , X ³ , X ⁴ )
X ² is C or N;
X ³ is C, N, S or O;
X ⁴ is C or N,
Basis

(In the formula, * indicates a binding site with an aminocarbonyl group, and ** indicates a binding site with an A ¹ -group)
To form
Provided that in the case of two additional heteroatoms, both are selected to be N, or one is N and one (except X ² ) is O;
X ³ and X ⁴ when having the meaning of C or N may carry further substituents,
The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof. X ² is C;
X ³ is O or S;
X ⁴ is N or C ,
Basis

Or

(In the formula, * indicates a binding site with an aminocarbonyl group, and ** indicates a binding site with an A ¹ -group)
Respectively;
X ⁴ may have a further substituent,
The compound according to claim 6 or a pharmaceutically acceptable salt thereof. The following formula

8. A compound according to any one of claims 3 to 7, or a pharmaceutically acceptable salt thereof, which forms a compound according to. X ² and X ³ are both N ,
Basis

(In the formula, * indicates a binding site with an aminocarbonyl group, and ** indicates a binding site with an A ¹ -group)
To form;
X ¹ and X ⁴ are C;
X ¹ and/or X ⁴ may have a further substituent;
Or X ⁴ is also N,
Basis

(In the formula, * indicates a binding site with an aminocarbonyl group, and ** indicates a binding site with an A ¹ -group)
To form;
X ¹ may have a further substituent,
The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof. X ¹ , X ² and X ⁴ are N,
X ³ is C,
Basis

(In the formula, * indicates a binding site with an aminocarbonyl group, and ** indicates a binding site with an A ¹ -group)
To form;
X ³ may have a further substituent,
The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof. X ¹ is O or S,
X ² is C;
X ³ is N;
X ⁴ is C,
Y ¹ represents -hydrogen, or an optional substituent to -X ⁴ ;
Basis

Or

(In the formula, * indicates a binding site with an aminocarbonyl group, and ** indicates a binding site with an A ¹ -group)
Respectively,
The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof. X ^{1, X 3} and the further substituent of ^{X 4} - halogen,及 Beauty <br/> - alkyl optionally substituted,
The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from the group consisting of: The compound according to any one of claims 1 to 12, wherein n is 1, and/or Q is H, and/or R ¹ is H, or a pharmaceutically acceptable salt thereof. A ¹ and A ² are optionally substituted alkanediyl, are the same or different, and are independently selected from optionally substituted --methylene and --ethane-1,2-diyl. Or A ¹ and R ³ together with the nitrogen atom to which they are attached form an optionally substituted 4-membered aliphatic monocyclic ring,
The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof. A compound according to claim 1 selected from:

Or a pharmaceutically acceptable salt thereof. formula

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, which comprises: A compound according to any one of claims 1 to 16 for use as a medicament. 18. A compound according to any one of claims 1 to 17 for use as a ferroportin inhibitor or for use in inhibiting ferroportin mediated iron transport. 19. A compound according to any one of claims 1 to 18 for use in the prevention and/or treatment of disorders of iron metabolism leading to elevated iron levels or increased iron absorption, and/or iron overload. Thalassemia (including α-thalassemia, β-thalassemia and δ-thalassemia), abnormal hemoglobinosis, hemoglobin E disease, hemoglobin H disease, hemochromatosis, hemolytic anemia (particularly sickle cell anemia or congenital erythropoietic anemia). For use in the prophylaxis and/or treatment of diseases associated with elevated iron levels, increased iron uptake or iron overload or caused by elevated iron levels, increased iron uptake or iron overload, Item 20. The compound according to any one of items 1 to 19. Diseases associated with ineffective erythropoiesis, such as myelodysplastic syndrome (MDS, myelodysplasia), polycythemia vera and congenital erythropoietic anemia; and/or diseases caused by reduced hepcidin levels; and/or bacterial vibrio In an adjunct therapy by limiting the amount of iron available to pathogenic microorganisms such as Vibrio vulnificus, infection caused by said pathogenic microorganisms; and/or deposition or increase of iron in tissues or cells 21. A compound according to any one of claims 1 to 20 for use in the prevention and/or treatment of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease by limiting. For use in the prevention and/or treatment of radicals, reactive oxygen species (ROS) and oxidative stress formation; and/or heart, liver and endocrine damage caused by iron overload; and/or inflammation induced by excess iron 22. The compound according to any one of claims 1 to 21. 23. A method according to any one of claims 1 to 22 for use in a combination therapy comprising co-administration of a compound according to any one of claims 1 to 22 and at least one further pharmaceutically active compound. A compound as described:
23. The co-administration of said combination therapy is carried out in a fixed dose combination therapy by co-administration of a compound according to any one of claims 1 to 22 and at least one further pharmaceutically active compound in a fixed dose formulation. may be cracking; or the co-administration of the combination therapy, by sequential use of the individual compounds distributed over co-administration or a certain time of the individual compounds from claim 1 in free dose of each compound 22 May be carried out in a free dose combination therapy by co-administration of the compound according to any one of the above and said at least one further pharmaceutically active compound; and one or more other pharmaceutically active compounds. A compound selected from T mprss6-ASO, an iron chelator, curcumin, SSP-004184, deferitrin, deferasirox, deferoxamine and/or deferiprone, an active compound for reducing iron overload; Antioxidants (such as n-acetylcysteine); Antidiabetic agents (such as GLP-1 receptor agonists); Antibiotics (such as vancomycin (Van) or tobramycin); Antimalarial agents; Anticancer agents; Antifungal agents; Neurodegenerative diseases (Alzheimer's disease Disease and Parkinson's disease) (including, for example, dopamine agonists such as levodopa); antiviral drugs (such as interferon α or ribavirin); immunosuppressants (such as cyclosporin A or cyclosporin A derivatives); iron supplements; vitamin supplements A compound selected from pharmaceutically active compounds selected from erythropoiesis stimulating agents; anti-inflammatory biologics; antithrombotic agents; statins; pressor agents; and inotropic compounds.

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